Heteroaryl linked quinolinyl modulators of RORγt

ABSTRACT

The present invention comprises compounds of Formula I. 
                         
wherein:
 
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are defined in the specification.
 
     The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim  1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Application No. 61/714,368, filed on Oct. 16, 2012, and U.S. Application No. 61/725,520, filed on Nov. 13, 2012, each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The invention is directed to substituted quinoline compounds, which are modulators of the nuclear receptor RORγt, pharmaceutical compositions, and methods for use thereof. More particularly, the RORγt modulators are useful for preventing, treating or ameliorating an RORγt mediated inflammatory syndrome, disorder or disease.

BACKGROUND OF THE INVENTION

Retinoic acid-related nuclear receptor gamma t (RORγt) is a nuclear receptor, exclusively expressed in cells of the immune system, and a key transcription factor driving Th17 cell differentiation. Th17 cells are a subset of CD4⁺ T cells, expressing CCR6 on their surface to mediate their migration to sites of inflammation, and dependent on IL-23 stimulation, through the IL-23 receptor, for their maintenance and expansion. Th17 cells produce several proinflammatory cytokines including IL-17A, IL-17F, IL-21, and IL-22 (Korn, T., E. Bettelli, et al. (2009). “IL-17 and Th17 Cells.” Annu Rev Immunol 27: 485-517.), which stimulate tissue cells to produce a panel of inflammatory chemokines, cytokines and metalloproteases, and promote recruitment of granulocytes (Kolls, J. K. and A. Linden (2004). “Interleukin-17 family members and inflammation.” Immunity 21(4): 467-76; Stamp, L. K., M. J. James, et al. (2004). “Interleukin-17: the missing link between T-cell accumulation and effector cell actions in rheumatoid arthritis” Immunol Cell Biol 82(1): 1-9). Th17 cells have been shown to be the major pathogenic population in several models of autoimmune inflammation, including collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) (Dong, C. (2006). “Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells.” Nat Rev Immunol 6(4): 329-33; McKenzie, B. S., R. A. Kastelein, et al. (2006). “Understanding the IL-23-IL-17 immune pathway.” Trends Immunol 27(1): 17-23.). RORγt-deficient mice are healthy and reproduce normally, but have shown impaired Th17 cell differentiation in vitro, a significantly reduced Th17 cell population in vivo, and decreased susceptibility to EAE (Ivanov, II, B. S. McKenzie, et al. (2006). “The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.” Cell 126(6): 1121-33.). Mice deficient for IL-23, a cytokine required for Th17 cell survival, fail to produce Th17 cells and are resistant to EAE, CIA, and inflammatory bowel disease (IBD) (Cua, D. J., J. Sherlock, et al. (2003). “Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.” Nature 421(6924): 744-8.; Langrish, C. L., Y. Chen, et al. (2005). “IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.” J Exp Med 201(2): 233-40; Yen, D., J. Cheung, et al. (2006). “IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.” J Clin Invest 116(5): 1310-6.). Consistent with these findings, an anti-IL23-specific monoclonal antibody blocks development of psoriasis-like inflammation in a murine disease model (Tonel, G., C. Conrad, et al. “Cutting edge: A critical functional role for IL-23 in psoriasis.” J Immunol 185(10): 5688-91).

In humans, a number of observations support the role of the IL-23/Th17 pathway in the pathogenesis of inflammatory diseases. IL-17, the key cytokine produced by Th17 cells, is expressed at elevated levels in a variety of allergic and autoimmune diseases (Barczyk, A., W. Pierzchala, et al. (2003). “Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine.” Respir Med 97(6): 726-33.; Fujino, S., A. Andoh, et al. (2003). “Increased expression of interleukin 17 in inflammatory bowel disease.” Gut 52(1): 65-70.; Lock, C., G. Hermans, et al. (2002). “Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.” Nat Med 8(5): 500-8.; Krueger, J. G., S. Fretzin, et al. “IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis.” J Allergy Clin Immunol 130(1): 145-154 e9.). Furthermore, human genetic studies have shown association of polymorphisms in the genes for Th17 cell-surface receptors, IL-23R and CCR6, with susceptibility to IBD, multiple sclerosis (MS), rheumatoid arthritis (RA) and psoriasis (Gazouli, M., I. Pachoula, et al. “NOD2/CARD15, ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn's disease.” World J Gastroenterol 16(14): 1753-8., Nunez, C., B. Dema, et al. (2008). “IL23R: a susceptibility locus for celiac disease and multiple sclerosis?” Genes Immun 9(4): 289-93.; Bowes, J. and A. Barton “The genetics of psoriatic arthritis: lessons from genome-wide association studies.” Discov Med 10(52): 177-83; Kochi, Y., Y. Okada, et al. “A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility.” Nat Genet. 42(6): 515-9.).

Ustekinumab (Stelara®), an anti-p40 monoclonal antibody blocking both IL-12 and IL-23, is approved for the treatment of adult patients (18 years or older), with moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy. Currently, monoclonal antibodies specifically targeting only IL-23, to more selectively inhibit the Th17 subset, are also in clinical development for psoriasis (Garber K. (2011). “Psoriasis: from bed to bench and back” Nat Biotech 29, 563-566), further implicating the important role of the IL-23- and RORγt-driven Th17 pathway in this disease. Results from recent phase II clinical studies strongly support this hypothesis, as anti-IL-17 receptor and anti-IL-17 therapeutic antibodies both demonstrated high levels of efficacy in patients with chronic psoriasis (Papp, K. A., “Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.” N Engl J Med 2012 366(13): 1181-9.; Leonardi, C., R. Matheson, et al. “Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.” N Engl J Med 366(13): 1190-9.). Anti-IL-17 antibodies have also demonstrated clinically relevant responses in early trials in RA and uveitis (Hueber, W., Patel, D. D., Dryja, T., Wright, A. M., Koroleva, I., Bruin, G., Antoni, C., Draelos, Z., Gold, M. H., Durez, P., Tak, P. P., Gomez-Reino, J. J., Foster, C. S., Kim, R. Y., Samson, C. M., Falk, N. S., Chu, D. S., Callanan, D., Nguyen, Q. D., Rose, K., Haider, A., Di Padova, F. (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2, 5272.).

All the above evidence supports inhibition of the Th17 pathway by modulating RORγt activity as an effective strategy for the treatment of immune-mediated inflammatory diseases.

SUMMARY OF THE INVENTION

The present invention comprises compounds of Formula I.

wherein:

-   -   R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,         pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl,         piperidinyl, quinazolinyl, cinnolinyl, benzothiazolyl,         indazolyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl,         phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl,         benzimidazolyl, indolyl, thiadiazolyl, oxadiazolyl or         quinolinyl; wherein said pyridyl, pyridyl-N-oxide, pyrazinyl,         pyrimidinyl, pyridazyl, piperidinyl, quinazolinyl, cinnolinyl,         benzothiazolyl, indazolyl, imidazolyl, phenyl, thiophenyl,         benzoxazolyl, benzimidazolyl, indolyl, quinolinyl, and pyrazolyl         are optionally substituted with C(O)C₍₁₋₄₎alkyl, C(O)NH₂,         C(O)NHC₍₁₋₂₎alkyl, C(O)N(C₍₁₋₂₎alkyl)₂, NHC(O)C₍₁₋₄₎alkyl,         NHSO₂C₍₁₋₄₎alkyl, C₍₁₋₄₎alkyl, CF₃, CH₂CF₃, Cl, F, —CN,         OC₍₁₋₄₎alkyl, N(C₍₁₋₄₎alkyl)₂, —(CH₂)₃OCH₃, SC₍₁₋₄₎alkyl, OH,         CO₂H, CO₂C₍₁₋₄₎alkyl, C(O)CF₃, SO₂CF₃, OCF₃, OCHF₂, SO₂CH₃,         SO₂NH₂, SO₂NHC₍₁₋₂₎alkyl, SO₂N(C₍₁₋₂₎alkyl)₂, C(O)NHSO₂CH₃, or         OCH₂OCH₃; and optionally substituted with up to two additional         substituents independently selected from the group consisting of         Cl, C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, and F; and         wherein said triazolyl, oxazolyl, isoxazolyl, pyrrolyl, and         thiazolyl are optionally substituted with up to two substituents         independently selected from the group consisting of SO₂CH₃,         SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃,         F, Cl, and C₍₁₋₂₎alkyl; and said thiadiazolyl and oxadiazolyl         are optionally substituted with C₍₁₋₂₎alkyl; and said pyridyl,         pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl are         optionally substituted with up to three additional substituents         independently selected from the group consisting of         C(O)NHC₍₁₋₂₎alkyl, C(O)N(C₍₁₋₂₎alkyl)₂, NHC(O)C₍₁₋₄₎alkyl,         NHSO₂C₍₁₋₄₎alkyl, C(O)CF₃, SO₂CF₃, SO₂NHC₍₁₋₂₎alkyl,         SO₂N(C₍₁₋₂₎alkyl)₂, C(O)NHSO₂CH₃, SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN,         OC₍₁₋₄₎alkyl, (CH₂)₍₂₋₃₎OCH₃ (including —(CH₂)₃OCH₃),         SC₍₁₋₄₎alkyl, CF₃, F, Cl, and C₍₁₋₄₎alkyl;

R² is triazolyl, pyridyl, pyridyl-N-oxide, pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C₍₁₋₃₎alkyl-piperidinyl, thiazolyl, pyridazyl, pyrazinyl, 1-(3-methoxypropyl)-imidazolyl, thiadiazolyl, oxadiazolyl, or imidazolyl; wherein said imidazolyl is optionally substituted with up to three additional substituents independently selected from the group consisting of C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, F, and Cl; and said pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl, are optionally substituted with up to three additional substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, or C₍₁₋₂₎alkyl; and said triazolyl, thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl; and said thiadiazolyl and oxadiazolyl are optionally substituted with C₍₁₋₂₎alkyl; and said pyrazolyl is optionally substituted with up to three CH₃ groups;

-   -   R³ is H, OH, OCH₃, or NH₂;     -   R⁴ is H, or F;     -   R⁵ is H, Cl, —CN, CF₃, SC₍₁₋₄₎alkyl, OC₍₁₋₄₎alkyl, OH,         C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₄₎alkyl), N(C₍₁₋₄₎alkyl)₂, or         4-hydroxy-piperidinyl;     -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl,         —N(CO₂C(CH₃)₃)phenyl, N(COCH₃)phenyl, —O-pyridyl, —NHpyridyl,         —N(C₍₁₋₃₎alkyl)pyridyl, N(CO₂C(CH₃)₃)pyridyl, N(COCH₃)pyridyl,         —O-pyrimidinyl, —NHpyrimidinyl, —N(C₍₁₋₃₎alkyl)pyrimidinyl,         N(CO₂C(CH₃)₃)pyrimidinyl, N(COCH₃)pyrimidinyl, —O-pyridazyl,         —NHpyridazyl, —N(C₍₁₋₃₎alkyl)pyridazyl, N(CO₂C(CH₃)₃)pyridazyl,         N(COCH₃)pyridazyl, —O-pyrazinyl, —NHpyrazinyl,         —N(C₍₁₋₃₎alkyl)pyrazinyl, N(CO₂C(CH₃)₃)pyrazinyl, or         N(COCH₃)pyrazinyl; wherein said pyrimidinyl, pyridazyl, or         pyrazinyl are optionally substituted with Cl, F, CH₃, SCH₃,         OC₍₁₋₄₎alkyl, —CN, CONH₂, SO₂NH₂, or SO₂CH₃; and wherein said         phenyl or said pyridyl is optionally substituted up to two times         with OCF₃, SO₂C₍₁₋₄₎alkyl, CF₃, CHF₂, pyrazolyl, triazolyl,         imidazolyl, tetrazolyl, oxazolyl, thiazolyl, C₍₁₋₄₎alkyl,         C₍₃₋₄₎cycloalkyl, OC₍₁₋₄₎alkyl, N(CH₃)₂, SO₂NH₂, SO₂NHCH₃,         SO₂N(CH₃)₂, CONH₂, CONHCH₃, CON(CH₃)₂, Cl, F, —CN, CO₂H, OH,         CH₂OH, NHCOC₍₁₋₂₎alkyl, COC₍₁₋₂₎alkyl, SCH₃, CO₂C₍₁₋₄₎alkyl,         NH₂, NHC₍₁₋₂₎alkyl, or OCH₂CF₃; wherein the selection of each         optional substituent is independent; and wherein said pyrazolyl,         triazolyl, imidazolyl, tetrazolyl, oxazolyl, and thiazolyl are         optionally substituted with CH₃;

R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₄₎alkylCF₃, OCF₃, OCHF₂, OCH₂CH₂OC₍₁₋₄₎alkyl, CF₃, SCH₃, C₍₁₋₄₎alkylNA¹A² (including CH₂NA¹A²), CH₂OC₍₂₋₃₎alkylNA¹A², NA¹A², C(O)NA¹A², CH₂NHC₍₂₋₃₎alkylNA¹A², CH₂N(CH₃)C₍₂₋₃₎alkylNA¹A², NHC₍₂₋₃₎alkylNA¹A², N(CH₃)C₍₂₋₄₎alkylNA¹A², OC₍₂₋₄₎alkylNA¹A², OC₍₁₋₄₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl, phenyl, thiophenyl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, or pyrimidinyl; wherein said phenyl, thiophenyl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, and pyrimidinyl are optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, CH₃, CF₃, and OCH₃;

-   -   A¹ is H, or C₍₁₋₄₎alkyl;     -   A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH,         C(O)C₍₁₋₄₎alkyl, or OC₍₁₋₄₎alkyl; or A¹ and A² may be taken         together with their attached nitrogen to form a ring selected         from the group consisting of:

-   -   R_(a) is H, OC₍₁₋₄₎alkyl, CH₂OH, NH(CH₃), N(CH₃)₂, NH₂, CH₃, F,         CF₃, SO₂CH₃, or OH;     -   R_(b) is H, CO₂C(CH₃)₃, C₍₁₋₄₎alkyl, C(O)C₍₁₋₄₎alkyl,         SO₂C₍₁₋₄₎alkyl, CH₂CH₂CF₃, CH₂CF₃, CH₂-cyclopropyl, phenyl,         CH₂-phenyl, or C₍₃₋₆₎cycloalkyl;     -   R⁸ is H, C₍₁₋₃₎alkyl (including CH₃), OC₍₁₋₃₎alkyl (including         OCH₃), CF₃, NH₂, NHCH₃, —CN, or F;     -   R⁹ is H, or F;         and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises compounds of Formula I.

wherein:

-   -   R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,         pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl,         piperidinyl, quinazolinyl, cinnolinyl, benzothiazolyl,         indazolyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl,         phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl,         benzimidazolyl, indolyl, thiadiazolyl, oxadiazolyl or         quinolinyl; wherein said pyridyl, pyridyl N-oxide, pyrazinyl,         pyrimidinyl, pyridazyl, piperidinyl, quinazolinyl, cinnolinyl,         benzothiazolyl, indazolyl, imidazolyl, phenyl, thiophenyl,         benzoxazolyl, benzimidazolyl, indolyl, quinolinyl, and pyrazolyl         are optionally substituted with C(O)C₍₁₋₄₎alkyl, C(O)NH₂,         C(O)NHC₍₁₋₂₎alkyl, C(O)N(C₍₁₋₂₎alkyl)₂, NHC(O)C₍₁₋₄₎alkyl,         NHSO₂C₍₁₋₄₎alkyl, C₍₁₋₄₎alkyl, CF₃, CH₂CF₃, Cl, F, —CN,         OC₍₁₋₄₎alkyl, N(C₍₁₋₄₎alkyl)₂, —(CH₂)₃OCH₃, SC₍₁₋₄₎alkyl, OH,         CO₂H, CO₂C₍₁₋₄₎alkyl, C(O)CF₃, SO₂CF₃, OCF₃, OCHF₂, SO₂CH₃,         SO₂NH₂, SO₂NHC₍₁₋₂₎alkyl, SO₂N(C₍₁₋₂₎alkyl)₂, C(O)NHSO₂CH₃, or         OCH₂OCH₃; and optionally substituted with up to two additional         substituents independently selected from the group consisting of         Cl, C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, and F; and         wherein said triazolyl, oxazolyl, isoxazolyl, pyrrolyl, and         thiazolyl are optionally substituted with up to two substituents         independently selected from the group consisting of SO₂CH₃,         SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃,         F, Cl, and C₍₁₋₂₎alkyl; and said thiadiazolyl and oxadiazolyl         are optionally substituted with C₍₁₋₂₎alkyl; and said pyridyl,         pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl are         optionally substituted with up to three additional substituents         independently selected from the group consisting of         C(O)NHC₍₁₋₂₎alkyl, C(O)N(C₍₁₋₂₎alkyl)₂, NHC(O)C₍₁₋₄₎alkyl,         NHSO₂C₍₁₋₄₎alkyl, C(O)CF₃, SO₂CF₃, SO₂NHC₍₁₋₂₎alkyl,         SO₂N(C₍₁₋₂₎alkyl)₂, C(O)NHSO₂CH₃, SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN,         OC₍₁₋₄₎alkyl, (CH₂)₍₂₋₃₎OCH₃ (including —(CH₂)₃OCH₃),         SC₍₁₋₄₎alkyl, CF₃, F, Cl, and C₍₁₋₄₎alkyl;     -   R² is triazolyl, pyridyl, pyridyl-N-oxide, pyrazolyl,         pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl,         1-H-piperidinyl, N-Boc-piperidinyl, N—C₍₁₋₃₎alkyl-piperidinyl,         thiazolyl, pyridazyl, pyrazinyl, 1-(3-methoxypropyl)-imidazolyl,         thiadiazolyl, oxadiazolyl, or imidazolyl; wherein said         imidazolyl is optionally substituted with up to three additional         substituents independently selected from the group consisting of         C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, F, and Cl; and said         pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl,         are optionally substituted with up to three additional         substituents independently selected from the group consisting of         SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃,         SCH₃, CF₃, F, Cl, or C₍₁₋₂₎alkyl; and said triazolyl, thiazolyl,         oxazolyl and isoxazolyl are optionally substituted with up to         two substituents independently selected from the group         consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl,         (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl; and said         thiadiazolyl and oxadiazolyl are optionally substituted with         C₍₁₋₂₎alkyl; and said pyrazolyl is optionally substituted with         up to three CH₃ groups;     -   R³ is H, OH, OCH₃, or NH₂;     -   R⁴ is H, or F;     -   R⁵ is H, Cl, —CN, CF₃, SC₍₁₋₄₎alkyl, OC₍₁₋₄₎alkyl, OH,         C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₄₎alkyl), N(C₍₁₋₄₎alkyl)₂, or         4-hydroxy-piperidinyl;     -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl,         —N(CO₂C(CH₃)₃)phenyl, N(COCH₃)phenyl, —O-pyridyl, —NHpyridyl,         —N(C₍₁₋₃₎alkyl)pyridyl, N(CO₂C(CH₃)₃)pyridyl, N(COCH₃)pyridyl,         —O-pyrimidinyl, —NHpyrimidinyl, —N(C₍₁₋₃₎alkyl)pyrimidinyl,         N(CO₂C(CH₃)₃)pyrimidinyl, N(COCH₃)pyrimidinyl, —O-pyridazyl,         —NHpyridazyl, —N(C₍₁₋₃₎alkyl)pyridazyl, N(CO₂C(CH₃)₃)pyridazyl,         N(COCH₃)pyridazyl, —O-pyrazinyl, —NHpyrazinyl,         —N(C₍₁₋₃₎alkyl)pyrazinyl, N(CO₂C(CH₃)₃)pyrazinyl, or         N(COCH₃)pyrazinyl; wherein said pyrimidinyl, pyridazyl, or         pyrazinyl are optionally substituted with Cl, F, CH₃, SCH₃,         OC₍₁₋₄₎alkyl, —CN, CONH₂, SO₂NH₂, or SO₂CH₃; and wherein said         phenyl or said pyridyl is optionally substituted up to two times         with OCF₃, SO₂C₍₁₋₄₎alkyl, CF₃, CHF₂, pyrazolyl, triazolyl,         imidazolyl, tetrazolyl, oxazolyl, thiazolyl, C₍₁₋₄₎alkyl,         C₍₃₋₄₎cycloalkyl, OC₍₁₋₄₎alkyl, N(CH₃)₂, SO₂NH₂, SO₂NHCH₃,         SO₂N(CH₃)₂, CONH₂, CONHCH₃, CON(CH₃)₂, Cl, F, —CN, CO₂H, OH,         CH₂OH, NHCOC₍₁₋₂₎alkyl, COC₍₁₋₂₎alkyl, SCH₃, CO₂C₍₁₋₄₎alkyl,         NH₂, NHC₍₁₋₂₎alkyl, or OCH₂CF₃; wherein the selection of each         optional substituent is independent; and wherein said pyrazolyl,         triazolyl, imidazolyl, tetrazolyl, oxazolyl, and thiazolyl are         optionally substituted with CH₃;     -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₄₎alkylCF₃, OCF₃, OCHF₂,         OCH₂CH₂OC₍₁₋₄₎alkyl, CF₃, SCH₃, C₍₁₋₄₎alkylNA¹A² (including         CH₂NA¹A²), CH₂OC₍₂₋₃₎alkylNA¹A², NA¹A², C(O)NA¹A²,         CH₂NHC₍₂₋₃₎alkylNA¹A², CH₂N(CH₃)C₍₂₋₃₎alkylNA¹A²,         NHC₍₂₋₃₎alkylNA¹A², N(CH₃)C₍₂₋₄₎alkylNA¹A², OC₍₂₋₄₎alkylNA¹A²,         OC₍₁₋₄₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl, phenyl, thiophenyl,         furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, or         pyrimidinyl; wherein said phenyl, thiophenyl, furyl, pyrazolyl,         imidazolyl, pyridyl, pyridazyl, pyrazinyl, and pyrimidinyl are         optionally substituted with up to three substituents         independently selected from the group consisting of F, Cl, CH₃,         CF₃, and OCH₃;     -   A¹ is H, or C₍₁₋₄₎alkyl;     -   A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH,         C(O)C₍₁₋₄₎alkyl, or OC₍₁₋₄₎alkyl; or A¹ and A² may be taken         together with their attached nitrogen to form a ring selected         from the group consisting of:

-   -   R_(a) is H, OC₍₁₋₄₎alkyl, CH₂OH, NH(CH₃), N(CH₃)₂, NH₂, CH₃, F,         CF₃, SO₂CH₃, or OH;     -   R_(b) is H, CO₂C(CH₃)₃, C₍₁₋₄₎alkyl, C(O)C₍₁₋₄₎alkyl,         SO₂C₍₁₋₄₎alkyl, CH₂CH₂CF₃, CH₂CF₃, CH₂-cyclopropyl, phenyl,         CH₂-phenyl, or C₍₃₋₆₎cycloalkyl;     -   R⁸ is H, C₍₁₋₃₎alkyl (including CH₃), OC₍₁₋₃₎alkyl (including         OCH₃), CF₃, NH₂, NHCH₃, —CN, or F;     -   R⁹ is H, or F;         and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

-   -   R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,         pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl,         piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl,         thiophenyl, benzoxazolyl, or quinolinyl; wherein said         piperidinyl, imidazolyl, phenyl, thiophenyl, benzoxazolyl,         pyrazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl,         pyridazyl, or quinolinyl are optionally substituted with         C(O)C₍₁₋₄₎alkyl, C(O)NH₂, C₍₁₋₄₎alkyl, CF₃, CH₂CF₃, Cl, F, —CN,         OC₍₁₋₄₎alkyl, N(C₍₁₋₄₎alkyl)₂, —(CH₂)₃OCH₃, SC₍₁₋₄₎alkyl, OH,         CO₂H, CO₂C₍₁₋₄₎alkyl, OCF₃, OCHF₂, SO₂CH₃, SO₂NH₂, or OCH₂OCH₃;         and optionally substituted with up to two additional         substituents independently selected from the group consisting of         Cl, C₍₁₋₂₎alkyl (including CH₃), SCH₃, OC₍₁₋₂₎alkyl (including         OCH₃), CF₃, —CN, and F; and wherein said triazolyl, oxazolyl,         isoxazolyl, pyrrolyl, and thiazolyl are optionally substituted         with up to two substituents independently selected from the         group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl,         (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl (including         CH₃); and said pyridyl, and pyridyl-N-oxide are optionally         substituted with up to three additional substituents         independently selected from the group consisting of SO₂CH₃,         SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₄₎alkyl, (CH₂)₍₂₋₃₎OCH₃ (including         —(CH₂)₃OCH₃), SC₍₁₋₄₎alkyl, CF₃, F, Cl, and C₍₁₋₄₎alkyl;     -   R² is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide,         1-methylpyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl         piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,         N—C₍₁₋₃₎alkyl-piperidinyl, (including         N—C₍₁₋₂₎alkyl-piperidinyl), thiazolyl, pyridazyl, pyrazinyl,         1-(3-methoxypropyl)-imidazolyl, or 1-C₍₁₋₂₎alkyl imidazolyl;         wherein said 1-C₍₁₋₂₎alkyl imidazolyl is optionally substituted         with up to two additional substituents independently selected         from the group consisting of C₍₁₋₂₎alkyl (including CH₃), SCH₃,         OC₍₁₋₂₎alkyl, CF₃, —CN, F, and Cl; and said pyridyl, and         pyridyl-N-oxide are optionally substituted with up to three         additional substituents independently selected from the group         consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl         (including OCH₃), (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and         C₍₁₋₂₎alkyl (including CH₃); and said thiazolyl, oxazolyl and         isoxazolyl are optionally substituted with up to two         substituents independently selected from the group consisting of         SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃,         SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl (including CH₃); and said         1-methyl pyrazolyl is optionally substituted with up to two         additional CH₃ groups;     -   R³ is H, OH, OCH₃, or NH₂;     -   R⁴ is H, or F;     -   R⁵ is H, Cl, —CN, CF₃, SC₍₁₋₄₎alkyl, OC₍₁₋₄₎alkyl, OH,         C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₄₎alkyl), N(C₍₁₋₄₎alkyl)₂, or         4-hydroxy-piperidinyl;     -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl,         —N(CO₂C(CH₃)₃)phenyl, N(COCH₃)phenyl, —O-pyridyl, —NHpyridyl,         —N(C₍₁₋₃₎alkyl)pyridyl, N(CO₂C(CH₃)₃)pyridyl, N(COCH₃)pyridyl,         —O-pyrimidinyl, —NHpyrimidinyl, —N(C₍₁₋₃₎alkyl)pyrimidinyl,         N(CO₂C(CH₃)₃)pyrimidinyl, N(COCH₃)pyrimidinyl, —O-pyridazyl,         —NHpyridazyl, —N(C₍₁₋₃₎alkyl)pyridazyl, N(CO₂C(CH₃)₃)pyridazyl,         N(COCH₃)pyridazyl, —O-pyrazinyl, —NHpyrazinyl,         —N(C₍₁₋₃₎alkyl)pyrazinyl, N(CO₂C(CH₃)₃)pyrazinyl, or         N(COCH₃)pyrazinyl; wherein said phenyl or said pyridyl is         optionally substituted with OCF₃, SO₂C₍₁₋₄₎alkyl (including         SO₂CH₃), CF₃, CHF₂, pyrazolyl, triazolyl, imidazolyl,         tetrazolyl, oxazolyl, thiazolyl, C₍₁₋₄₎alkyl (including CH₃),         C₍₃₋₄₎cycloalkyl, OC₍₁₋₄₎alkyl (including OCH₃), N(CH₃)₂,         SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂, CONH₂, CONHCH₃, CON(CH₃)₂, Cl, F,         —CN, CO₂H, OH, CH₂OH, NHCOC₍₁₋₂₎alkyl (including NHCOCH₃),         COC₍₁₋₂₎alkyl (including C(O)CH₃), or SCH₃;     -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₄₎alkylCF₃,         OCH₂CH₂OC₍₁₋₄₎alkyl, CF₃, SCH₃, CH₂NA¹A², CH₂OC₍₂₋₃₎alkylNA¹A²,         NA¹A², C(O)NA¹A², N(CH₃)C₍₂₋₄₎alkylNA¹A², OC₍₂₋₄₎alkylNA¹A²,         OC₍₁₋₄₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl, furyl, pyrazolyl,         imidazolyl, pyridyl, pyridazyl, pyrazinyl, or pyrimidinyl;         wherein said imidazolyl or pyrazolyl is optionally substituted         with one CH₃ group;     -   A¹ is H, or C₍₁₋₄₎alkyl;     -   A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH,         C(O)C₍₁₋₄₎alkyl, or OC₍₁₋₄₎alkyl; or A¹ and A² may be taken         together with their attached nitrogen to form a ring selected         from the group consisting of:

-   -   R_(a) is H, OC₍₁₋₄₎alkyl, CH₂OH, NH(CH₃), N(CH₃)₂, NH₂, CH₃, F,         or OH;     -   R_(b) is H, CO₂C(CH₃)₃, C₍₁₋₄₎alkyl, C(O)C₍₁₋₄₎alkyl (including         C(O)CH₃), SO₂C₍₁₋₄₎alkyl, CH₂CH₂CF₃, CH₂CF₃, CH₂-cyclopropyl,         phenyl, CH₂-phenyl, or C₍₃₋₆₎cycloalkyl;     -   R⁸ is H, CH₃, OCH₃, or F;     -   R⁹ is H, or F;         and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

-   -   R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,         pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl,         piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl,         thiophenyl, benzoxazolyl, or quinolinyl; wherein said         piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl,         thiophenyl, benzoxazolyl, and pyrazolyl are optionally         substituted with C(O)C₍₁₋₄₎alkyl (including C(O)CH₃), C(O)NH₂,         C₍₁₋₄₎alkyl (including CH₃, and CH₂CH₃), CF₃, CH₂CF₃, Cl, F,         —CN, OC₍₁₋₄₎alkyl (including OCH₃), N(C₍₁₋₄₎alkyl)₂ (including         N(CH₃)₂), —(CH₂)₃OCH₃, SC₍₁₋₄₎alkyl (including SCH₃), OH, CO₂H,         CO₂C₍₁₋₄₎alkyl (including CO₂C(CH₃)₃), OCF₃, OCHF₂, SO₂CH₃,         SO₂NH₂, or OCH₂OCH₃; and optionally substituted with up to two         additional substituents independently selected from the group         consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl,         oxazolyl, isoxazolyl, and thiazolyl are optionally substituted         with one or two CH₃ groups;     -   R² is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide,         1-methylpyrazolyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl,         N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,         N—C₍₁₋₂₎alkyl-piperidinyl, thiazolyl, pyridazyl,         1-(3-methoxypropyl)-imidazolyl, or 1-C₍₁₋₂₎alkyl imidazolyl;         wherein said 1-C₍₁₋₂₎alkyl imidazolyl is optionally substituted         with up to two additional CH₃ groups, or one substituent         selected from the group consisting of SCH₃, and Cl; and said         pyridyl, and pyridyl-N-oxide are optionally substituted with up         to two substitutents independently selected from the group         consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OCH₃, CF₃, Cl, and         CH₃; and said thiazolyl, oxazolyl and isoxazolyl are optionally         substituted with up to two CH₃ groups; and said         1-methylpyrazolyl is optionally substituted with up to two         additional CH₃ groups;     -   R³ is H, OH, OCH₃, or NH₂;     -   R⁴ is H, or F;     -   R⁵ is H, Cl, —CN, CF₃, SC₍₁₋₄₎alkyl (including SCH₃),         OC₍₁₋₄₎alkyl (including OC₍₁₋₃₎alkyl), OH, C₍₁₋₄₎alkyl,         N(CH₃)OCH₃, NH(C₍₁₋₄₎alkyl) (including NH(C₍₁₋₂₎alkyl)),         N(C₍₁₋₄₎alkyl)₂ (including N(C₍₁₋₂₎alkyl)₂), or         4-hydroxy-piperidinyl;     -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl,         —N(CO₂C(CH₃)₃)phenyl, N(COCH₃)phenyl, —O-pyridyl, —NHpyridyl,         —N(C₍₁₋₃₎alkyl)pyridyl, N(CO₂C(CH₃)₃)pyridyl, N(COCH₃)pyridyl,         —O-pyrimidinyl, —NHpyrimidinyl, —N(C₍₁₋₃₎alkyl)pyrimidinyl,         N(CO₂C(CH₃)₃)pyrimidinyl, N(COCH₃)pyrimidinyl, —O-pyridazyl,         —NHpyridazyl, —N(C₍₁₋₃₎alkyl)pyridazyl, N(CO₂C(CH₃)₃)pyridazyl,         N(COCH₃)pyridazyl, —O-pyrazinyl, —NHpyrazinyl,         —N(C₍₁₋₃₎alkyl)pyrazinyl, N(CO₂C(CH₃)₃)pyrazinyl, or         N(COCH₃)pyrazinyl wherein said phenyl or said pyridyl is         optionally substituted with OCF₃, SO₂CH₃, CF₃, CHF₂, pyrazolyl,         triazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, CH₃,         OCH₃, N(CH₃)₂, SO₂NH₂, CONH₂, Cl, F, —CN, CO₂H, OH, CH₂OH,         NHCOCH₃, or COCH₃;     -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₄₎alkylCF₃ (including         OCH₂CF₃), OCH₂CH₂OC₍₁₋₄₎alkyl (including OCH₂CH₂OCH₃), CF₃,         SCH₃, NA¹A², C(O)NA¹A² (including C(O)NHCH₃),         N(CH₃)C₍₂₋₄₎alkylNA¹A² (including N(CH₃)CH₂CH₂NA¹A²),         OC₍₂₋₄₎alkylNA¹A² (including OCH₂CH₂NA¹A²), OC₍₁₋₄₎alkyl         (including OC₍₁₋₃₎alkyl), OCH₂-(1-methyl)-imidazol-2-yl,         imidazolyl, furyl, pyrazolyl, pyridyl, or pyrimidinyl; wherein         said imidazolyl or pyrazolyl can be optionally substituted with         one CH₃ group;     -   A¹ is H, or C₍₁₋₄₎alkyl;     -   A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH,         C(O)C₍₁₋₄₎alkyl (including C(O)C₍₁₋₂₎alkyl), or OC₍₁₋₄₎alkyl         (including OCH₃); or A¹ and A² may be taken together with their         attached nitrogen to form a ring selected from the group         consisting of:

-   -   R_(a) is H, F, OC₍₁₋₄₎alkyl (including OCH₃), or OH;     -   R_(b) is C₍₁₋₄₎alkyl (including CH₃), C(O)CH₃, or phenyl;     -   R⁸ is H, CH₃, OCH₃, or F;     -   R⁹ is H, or F;         and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

-   -   R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,         pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl,         piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl,         thiophenyl, benzoxazolyl, or quinolinyl; wherein said         piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl,         thiophenyl, benzoxazolyl, and pyrazolyl are optionally         substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl,         F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃,         or OCH₂OCH₃; and optionally substituted with up to two         additional substituents independently selected from the group         consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl,         oxazolyl, isoxazolyl, and thiazolyl are optionally substituted         with one or two CH₃ groups;     -   R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide,         1-methylpyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl,         isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl,         N-Boc-piperidinyl, N—C₍₁₋₂₎alkyl-piperidinyl, thiazol-5-yl,         1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl         imidazol-5-yl (including 1-ethyl imidazol-5-yl and 1-methyl         imidazol-5-yl); wherein said 1-C₍₁₋₂₎alkyl imidazol-5-yl         (including 1-methyl imidazol-5-yl) is optionally substituted         with up to two additional CH₃ groups, or one substituent         selected from the group consisting of SCH₃, and Cl; and said         pyridyl, and pyridyl-N-oxide are optionally substituted with up         to two substituents independently selected from the group         consisting of C(O)NH₂, —CN, OCH₃, CF₃, Cl, and CH₃; and said         thiazol-5-yl, and said isoxazolyl are optionally substituted         with up to two CH₃ groups; and said 1-methylpyrazol-4-yl is         optionally substituted with up to two additional CH₃ groups;     -   R³ is H, OH, OCH₃, or NH₂;     -   R⁴ is H, or F;     -   R⁵ is H, Cl, —CN, CF₃, SCH₃, OC₍₁₋₃₎alkyl (including         OC₍₁₋₂₎alkyl), OH, C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl),         N(C₍₁₋₂₎alkyl)₂, or 4-hydroxy-piperidinyl;     -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl,         —N(CO₂C(CH₃)₃)phenyl, —O-pyridyl, —NHpyridyl,         —N(C₍₁₋₃₎alkyl)pyridyl, or —N(CO₂C(CH₃)₃)pyridyl wherein said         phenyl or said pyridyl is optionally substituted with OCF₃,         SO₂CH₃, CF₃, CHF₂, imidazol-1-yl, pyrazol-1-yl,         1,2,4-triazol-1-yl, CH₃, OCH₃, Cl, F, or —CN;     -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl (including C₍₁₋₃₎alkyl), OCH₂CF₃,         OCH₂CH₂OCH₃, CF₃, SCH₃, NA¹A², C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A²,         OCH₂CH₂NA¹A², OC₍₁₋₃₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl,         imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or         pyrimidin-5-yl; wherein said imidazolyl or pyrazolyl is         optionally substituted with one CH₃ group;     -   A¹ is H, or C₍₁₋₄₎alkyl;     -   A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH,         C(O)C₍₁₋₂₎alkyl, or OCH₃; or A¹ and A² may be taken together         with their attached nitrogen to form a ring selected from the         group consisting of:

-   -   R_(a) is H, F, OCH₃, or OH;     -   R_(b) is CH₃, or phenyl;     -   R⁸ is H, CH₃, OCH₃, or F;     -   R⁹ is H, or F;         and pharmaceutically acceptable salts thereof.

In another embodiment of the invention:

-   -   R¹ is thiazolyl, pyridyl, or phenyl; wherein said pyridyl, and         said phenyl, are optionally substituted with CF₃, Cl, or OCH₃;     -   R² is pyrid-3-yl, or 1-methyl imidazol-5-yl;     -   R³ is OH;     -   R⁴ is H;     -   R⁵ is Cl, —CN, CF₃, or OC₍₁₋₂₎alkyl;     -   R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl, or         —N(CO₂C(CH₃)₃)phenyl; wherein said —O-phenyl is optionally         substituted with Cl, F, or —CN;     -   R⁷ is Cl, —CN, NA¹A², or OC₍₁₋₂₎alkyl;     -   A¹ is C₍₁₋₂₎alkyl;     -   A² is C₍₁₋₂₎alkyl, or CH₂CH₂OCH₃; or A¹ and A² may be taken         together with their attached nitrogen to form a ring selected         from the group consisting of:

-   -   R⁸ is H;     -   R⁹ is H;         and pharmaceutically acceptable salts thereof.

Another embodiment of the invention is a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention comprises a compound of Formula I and a pharmaceutically acceptable carrier.

The present invention also provides a method for preventing, treating or ameliorating an RORγt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, ankylosing spondylitis, nephritis, organ allograft rejection, fibroid lung, systic fibrosis, renal insufficiency, diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphylococcia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, systemic lupus erythematosus, asthma, allergic asthma, steroid resistant asthma, neutrophilic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and carcinomas of the bladder, breast, cervix, colon, lung, prostate, or stomach comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of the compound of Formula I or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis, comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is psoriasis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is chronic obstructive pulmonary disorder comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is psoriatic arthritis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is ankylosing spondylitis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is Crohn's disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is ulcerative colitis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is neutrophilic asthma comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is steroid resistant asthma comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is multiple sclerosis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is systemic lupus erythematosus comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The invention also relates to methods of modulating RORγt activity in a mammal by administration of an effective amount of at least one compound of Formula I.

The present invention provides a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: inflammatory bowel diseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, and systemic lupus erythematosus comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating an inflammatory bowel disease, wherein said inflammatory bowel disease is Crohn's disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating an inflammatory bowel diseases, wherein said inflammatory bowel disease is ulcerative colitis comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

Definitions

The term “administering” with respect to the methods of the invention, means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of Formula I or a form, composition or medicament thereof. Such methods include administering an effective amount of said compound, compound form, composition or medicament at different times during the course of a therapy or concurrently in a combination form. The methods of the invention are to be understood as embracing all known therapeutic treatment regimens.

The term “subject” refers to a patient, which may be animal, typically a mammal, typically a human, which has been the object of treatment, observation or experiment and is at risk of (or susceptible to) developing a syndrome, disorder or disease that is associated with abberant RORγt expression or RORγt overexpression, or a patient with an inflammatory condition that accompanies syndromes, disorders or diseases associated with abberant RORγt expression or RORγt overexpression.

The term “effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “alkyl” refers to both linear and branched chain radicals of up to 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Any alkyl group may be optionally substituted with one OCH₃, one OH, or up to two fluorine atoms.

The term “C_((a-b))” (where a and b are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive. For example, C₍₁₋₄₎ denotes a radical containing 1, 2, 3 or 4 carbon atoms.

The term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic or bicyclic hydrocarbon ring radical derived by the removal of one hydrogen atom from a single ring carbon atom. Typical cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Additional examples include C₍₃₋₆₎cycloalkyl, C₍₅₋₈₎cycloalkyl, decahydronaphthalenyl, and 2,3,4,5,6,7-hexahydro-1H-indenyl. Any cycloalkyl group may be optionally substituted with one OCH₃, one OH, or up to two fluorine atoms.

As used herein, the term “thiophenyl” is intended to describe the radical formed by removing a hydrogen atom from the molecule with the structure:

Pharmaceutically Acceptable Salts

Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and triethiodide. Organic or inorganic acids also include, and are not limited to, hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic, hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, saccharinic or trifluoroacetic acid.

Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine, piperidine, potassium, potassium-t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

Methods of Use

The present invention is directed to a method for preventing, treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof.

Since RORγt is an N-terminal isoform of RORγ, it is recognized that compounds of the present invention which are modulators of RORγt are likely to be modulators of RORγ as well. Therefore the mechanistic description “RORγt modulators” is intended to encompass RORγ modulators as well.

When employed as RORγt modulators, the compounds of the invention may be administered in an effective amount within the dosage range of about 0.5 mg to about 10 g, preferably between about 0.5 mg to about 5 g, in single or divided daily doses. The dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments.

It is also apparent to one skilled in the art that the therapeutically effective dose for compounds of the present invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

The compounds of Formula I may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents. Exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts and salts with amino acids such as arginine. Also, the basic nitrogen-containing groups may be quaternized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route. Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

The present invention also encompasses a method of making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention. Additionally, the present invention includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention.

Polymorphs and Solvates

Furthermore, the compounds of the present invention may have one or more polymorph or amorphous crystalline forms and as such are intended to be included in the scope of the invention. In addition, the compounds may form solvates, for example with water (i.e., hydrates) or common organic solvents. As used herein, the term “solvate” means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The term “solvate” is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

It is intended that the present invention include within its scope polymorphs and solvates of the compounds of the present invention. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the means for treating, ameliorating or preventing a syndrome, disorder or disease described herein with the compounds of the present invention or a polymorph or solvate thereof, which would obviously be included within the scope of the invention albeit not specifically disclosed.

In another embodiment, the invention relates to a compound as described in Formula I for use as a medicament.

In another embodiment, the invention relates to the use of a compound as described in Formula I for the preparation of a medicament for the treatment of a disease associated with an elevated or aberrant RORγt activity.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, Ed. H. Bundgaard, Elsevier, 1985.

Furthermore, it is intended that within the scope of the present invention, any element, in particular when mentioned in relation to a compound of Formula (I), shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise a radioactive isotope selected from the group of ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

Some compounds of the present invention may exist as atropisomers. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. It is to be understood that all such conformers and mixtures thereof are encompassed within the scope of the present invention.

Where the compounds according to this invention have at least one stereocenter, they may accordingly exist as enantiomers or diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

ABBREVIATIONS

Herein and throughout the application, the following abbreviations may be used.

-   Å angstrom -   Ac acetyl -   Boc tert-butyloxycarbonyl -   br broad -   Bu butyl -   n-BuLi n-butyl lithium -   d doublet -   dba dibenzylideneacetone -   DCM dichloromethane -   Dess-Martin periodinane     1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one -   DMAP dimethylaminopyridine -   DMF N,N-dimethylformamide -   DMSO dimethyl sulfoxide -   dppf (diphenylphosphino)ferrocene -   Eaton's Reagent 7.7 wt % phosphorus pentoxide solution in     methanesulfonic acid -   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride -   ESI electrospray ionization -   Et ethyl -   Et₂O diethyl ether -   EtOAc ethyl acetate -   EtOH ethyl alcohol -   Et₃SiCl chlorotriethylsilane -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium     hexafluorophosphate -   HPLC high pressure liquid chromatography -   Hz hertz -   i-PrOH isopropyl alcohol -   LCMS liquid chromatography-mass spectrometry -   m multiplet -   M molar (moles/liter) -   Meldrum's acid 2,2-dimethyl-1,3-dioxane-4,6-dione -   MeOH methanol -   MHz megahertz -   min minutes -   mL mililiters -   MTBE methyl tertiary butyl ether -   nm nanometers -   NaOiPr sodium isopropoxide -   NMR nuclear magnetic resonance -   Ph phenyl -   ppm parts per million -   Pr propyl -   q quartet -   s singlet -   TFA trifluoroacetic acid -   THF tetrahydrofuran -   TLC thin layer chromatography -   UV ultra-violet -   X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl     General Schemes:

Compounds of Formula I in the present invention can be synthesized in accordance with the general synthetic methods known to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.

Scheme 1 describes the preparation of 6-haloquinoline intermediates of Formula VI. Methyl 2-amino-5-halobenzoates II can undergo acylation with substituted acid chlorides III (R⁶ is substituted arylamino, heteroarylamino, aryloxy, or heteroaryloxy as described above), or can be condensed with substituted carboxylic acids IV using EDCI and a base, to form amide intermediates. The amide intermediates can be cyclized by treatment with a base, such as potassium bis(trimethylsilyl)amide, to afford 6-halo-4-hydroxyquinolin-2(1H)-ones V. Heating hydroxyquinolin-2(1H)-ones V with phosphorus oxychloride, neat or in a solvent such as acetonitrile, yields 2,4-dichloroquinolines VI. Displacement of the 2-Cl of 2,4-dichloroquinolines VI with sodium alkoxides can be accomplished in an alcoholic solvent such as methanol, ethanol or isopropanol or at elevated temperatures in a non-polar solvent such as toluene to provide substituted quinolines VI wherein R⁵ is Cl and R⁷ is Oalkyl (path 1). Additional intermediates of formula VI where R⁷ is N(alkyl)₂ can be obtained by displacement of the 2-Cl group of 2,4-dichloroquinolines VI with disubstituted amines, such as NHMe₂, NHEt₂, NHMeEt, or azetidine in a hot polar solvent, such as MeOH, EtOH, or DMF (path 2).

An alternative route to 6-haloquinolines VI where R⁶ is substituted arylamino or heteroarylamino is shown in Scheme 2. 4-Haloanilines VII can be heated with 2,2-dimethyl-1,3-dioxan-4,6-dione (Meldrum's acid) to form 3-((4-halophenyl)amino)-3-oxopropanoic acids VIII. Cyclization of VIII in Eaton's reagent at elevated temperature then affords 4-hydroxyquinolinone intermediates (Synth. Commun. 2010, 40, 732), which can be treated with (diacetoxyiodo)benzene and trifluoromethanesulfonic acid to yield 4-hydroxyquinolinone phenyliodoniumtrifluoromethane sulfonates IX (Org. React. 2001, 57, 327). Reaction of these intermediates with arylamines or heteroarylamines yields substituted 3-amino-4-hydroxyquinolinones X (Monatsh. Chem. 1984, 115 (2), 231), which may be heated in phosphorus oxychloride to afford 2,4-dichloroquinolines VI. In cases where R⁶ is a secondary amine, these intermediates may be further functionalized to form amides by reaction with an acid chloride and a tertiary amine base, or to form carbamates by reaction with a dialkyl dicarbonate, such as di-tert-butyl dicarbonate, and DMAP in a polar solvent such as THF or DMF.

Scheme 3 describes the synthesis of 2- and 4-trifluoromethylquinolines VI. Treatment of 1-halo-4-fluorobenzenes XI with lithium diisopropylamide at −78° C. followed by addition of ethyl trifluoroacetate gives 2-fluorophenyl-2,2,2-trifluoroethanones XII. Displacement of the 2-fluoro substituent in XII with sodium azide followed by reduction of azide intermediates, for example with tin (II) chloride dihydrate, yields anilines XIII. Acylation of anilines XIII with acid chlorides III or carboxylic acids IV and a coupling agent such as EDCI, in the presence of a base, such as triethylamine or potassium tert-butoxide, leads directly to cyclized quinolin-2(1H)-ones XIV. Heating 4-(trifluoromethyl)quinolin-2(1H)-ones XIV with phosphorus oxychloride in the presence of diisopropylethylamine yields 6-haloquinolines VI wherein R⁵ is CF₃ and R⁷ is Cl (path 1). 4-Chloro-2-(trifluoromethyl)quinolines can be prepared starting from 2-aminobenzoic acids XV (path 2). Cyclization of XV with substituted 1,1,1-trifluoropropan-2-ones in Eaton's reagent at elevated temperatures yields 4-hydroxy-2-(trifluoromethyl)quinolines XVI, which upon heating in phosphorus oxychloride yields 6-haloquinolines VI wherein R⁵ is C¹ and R⁷ is CF₃.

Scheme 4 illustrates methods for the preparation of 6-haloquinoline intermediates VI in which either R⁵ or R⁷ is hydrogen. Amides XVII, formed by acylation of anilines VII as previously described above, can be cyclized to quinolines VI wherein R⁵ is H and R⁷ is Cl by formylation using Vilsmeier-Haack conditions (POCl₃/DMF) followed by heating to promote ring cyclization (path 1). 6-Haloquinolines VI where R⁵ is C¹ and R⁷ is H can be prepared by the methods shown in paths 2,3 and 4. 4-Haloanilines VII can be reacted with in situ generated methoxymethylene Meldrum's acid to form enamines XVIII which can cyclize by heating in the range of 250-300° C. in a non-polar high-boiling solvent such as diphenyl ether, to provide 4-hydroxyquinolines XIX (Madrid, P. B. et al., Bioorg. Med. Chem. Lett., 2005, 15, 1015). 4-Hydroxyquinolines XIX may be nitrated at the 3-position by heating with nitric acid in an acidic solvent, such as propionic acid, to provide 3-nitro-4-hydroxyquinolines XX (path 3). Heating these intermediates with POCl₃ and reduction of the nitro group, for instance using tin(II) chloride dihydrate, provides 3-amino-4-chloroquinolines XXI. N-arylation or N-heteroarylation can be accomplished using aryl or heteroaryl boronic acids and a copper salt, such as Cu(OAc)₂, in the presence of a tertiary amine base. The resulting secondary amines can be further elaborated to 6-haloquinolines of Formula VI where is R⁵ is C¹, R⁶ is substituted arylamino or heteroarylamino, and R⁷ is H by N-alkylation or acylation with an alkyl halide or alkyl acid chloride and a base. Alternatively, 4-hydroxyquinolines XIX may be brominated at the 3-position by heating with N-bromosuccinamide in acetic acid to furnish 3-bromo-4-hydroxyquinolines XXII (path 4). Displacement of the 3-bromo substituent can be accomplished by heating with an aryl or heteroaryl potassium phenoxide salt in the presence of copper powder and copper (I) bromide in a polar solvent, such as DMF, as described in Collini, M. D. et al., US 20050131014. The resulting 4-hydroxyquinolines XXIII can be heated in POCl₃ to provide 6-haloquinolines VI where R⁵ is Cl, R⁶ is aryloxy or heteroaryloxy, and R⁷ is H.

Scheme 5 illustrates synthetic routes (path 1 to 6) to ketones of Formula XXVIII. In path 1, Weinreb amide XXV can be prepared from acids XXIV by reacting with N,O-dimethylhydroxylamine hydrochloride and 1,1-carbonyldiimidazole or with N,O-dimethylhydroxylamine hydrochloride in the presence of a base such as triethylamine or Hunig's base and a coupling reagent such as EDCI. The amides XXV can be further treated with Grignard reagents such as R²MgX (X is Br or Cl) that can be obtained commercially or preformed by treatment of R²Z with organometallic reagents such as i-PrMgCl or EtMgCl in THF. Alternatively, Weinreb amides XXV can be obtained from acyl chlorides XXIX and N,O-dimethylhydroxylamine hydrochloride by using triethylamine or pyridine as a base. 1-Methyl-1H-imidazole can be treated with one equivalent of n-BuLi and one equivalent of chlorotriethylsilane at −78° C. followed by an additional equivalent of n-BuLi, to which the Weinreb amides XXV can be added to yield ketones XXVIII wherein R² is imidazolyl (path 2).

In path 3, halogen and metal exchange of bromides or iodides XXVII with i-PrMgCl.LiCl or n-BuLi, followed by addition of aldehydes XXX affords alcohols XXXI. Oxidation of XXXI with Dess-Martin periodinane or MnO₂ can provide ketones XXVIII. In path 4, ketones XXVIII, where R² is triazolyl, can be prepared by treatment of 1-methyl-1H-1,2,3-triazole with n-BuLi followed by reaction with aldehydes XXX to yield alcohols XXXI, which could undergo oxidation with Dess-Martin periodinane or MnO₂. Path 5 exemplifies the preparation of symmetrical ketones XXVIII, wherein R¹ and R² are the same. As illustrated, an aryl or heteroaryl group containing an acidic proton XXXIX (Y═R¹ or R²) can be deprotonated in the presence of a strong base such as n-butyllithium once solubilized in a preferred solvent such as tetrahydrofuran at temperatures between 0 and −78° C. then added in excess to ethyl methoxy(methyl)carbamate to provide aryl ketones XXVIII wherein R¹ and R² are the same. Aryl or heteroaryl bromide or iodide XL can also be lithiated through a lithium/halogen exchange with n-butyllithium before adding in excess to ethyl methoxy(methyl)carbamate as previously described to provide symmetrical ketones XXVIII. Path 6, which employs palladium catalyzed cross-coupling of arylboronic acids XLI with acid chlorides XLII using K₃PO₄ as a base and (Ph₃P)₂PdCl₂ as a catalyst in a high boiling non-polar solvent such as toluene, can also be used to generate ketones XXVIII.

Scheme 6 illustrates synthetic routes leading to compounds of Formula I (paths 1 and 2). As illustrated in path 1, a mixture of the 6-haloquinolines VI in an appropriate solvent such as THF can be either premixed with the aryl ketones XXVIII at −78° C. followed by addition of n-BuLi or can be pretreated with n-BuLi at −78° C. prior to the addition of the aryl ketones XXVIII to afford the tertiary alcohols of Formula I, wherein R³ is OH. In path 2,6-iodoquinolines VI can be treated with i-PrMgCl followed by addition of ketones XXVIII to yield compounds of Formula I wherein R³ is OH.

An alternative route to compounds of Formula I is shown in Scheme 7. In path 1, treatment of 6-bromoquinolines VI with n-BuLi at −78° C. followed by addition of aldehydes XXX provides secondary alcohol quinolines XXXII, which can be oxidized to ketones XXXIII with Dess-Martin periodinane or MnO₂. Alternatively, ketones XXXIII may be prepared by treatment of 6-bromoquinolines VI with n-BuLi at −78° C. followed by quenching with DMF affording carboxaldehydes XXXIV. Ketones XXXIII can be obtained in a two-step process by addition of aldehydes XXXIV to a reaction mixture of aryl iodides XXXV and i-PrMgCl.LiCl followed by oxidation with MnO₂ (path 2). Halogen-metal exchange of aryl halides (iodide or bromide) XXVII with an organometallic reagent, such as n-BuLi, i-PrMgCl.LiCl, or EtMgCl, at an appropriate temperature, such as −78° C. or 0° C., followed by reaction with ketones XXXIII may afford tertiary alcohol quinolines of Formula I.

Scheme 8 illustrates methods used to synthesize compounds of Formula I wherein either the chlorine at R⁷ or at both R⁵ and R⁷ positions are replaced with nitrogen, oxygen, sulfur or alkyl groups. In paths 1 and 4, nucleophilic displacement of 2,4-dichloroquinolines I (R⁵ and R⁷ are Cl) with NaO(alkyl) or NaS(alkyl), such as NaOMe, NaSMe, NaOEt, or NaO^(i)Pr, in an appropriate solvent, such as MeOH, EtOH, i-PrOH or DMF at elevated temperatures or with substituted hydroxy reagents such as 2-methoxyethanol in the presence of a base like sodium hydride in a non-polar solvent such as toluene provides compounds of Formula I wherein R⁵ is Cl and R⁷ is O(alkyl), O(CH₂)₂OCH₃ or S(alkyl) and compounds of Formula I wherein R⁵ and R⁷ are O(alkyl) or S(alkyl). Likewise, nucleophilic displacement of 2,4-dichloroquinolines I (R⁵ and R⁷ are CO with primary or secondary alkyl amines, heterocyclic amines, or N,O-dimethylhydroxylamine in polar solvents such as MeOH, EtOH, Et₂NCHO, or DMF provides quinolines of Formula I (path 2) wherein R⁵ is NH(alkyl), N(alkyl)₂, N(CH₃)OCH₃, or Cl, and R⁷ is NH(alkyl), N(alkyl)₂, N(CH₃)OCH₃, NA¹A², NHC₍₂₋₃₎alkylNA¹A² or N(CH₃)C₍₂₋₄₎alkylNA¹A², wherein A¹ and A² are as defined above. Introduction of cyclic amides can be accomplished using Buchwald palladium catalyzed coupling conditions to provide compounds of Formula I, wherein R⁷ are rings such as azetidin-2-ones or pyrrolidin-2-ones. Replacement of chlorine at positions 2- and 4- of quinolines I (R⁵ and R⁷ are Cl) with alkyl groups could be carried out using Zn(alkyl)₂ in the presence of K₂CO₃ and a palladium catalyst, such as PdCl₂(dppf), to afford 2-alkyl and 2,4-dialkylquinolines I (path 3).

Synthetic routes to compounds of Formula I, wherein R⁵ is Cl or CN, and R⁷ is CN or aryl, are illustrated in Scheme 9. In path 1, cyanation of the 2,4-dichloroquinolines I with Zn(CN)₂ in the presence of Zn, a palladium catalyst, such as Pd₂ dba₃, and a ligand, such as dppf or X-phos, at high temperatures can provide 2-CN and 2,4-diCN quinolines I. The 2,4-dichloroquinolines I can also undergo Suzuki reactions with ArB(OH)₂ or ArB(OR)₂ and a palladium catalyst, such as PdCl₂(dppf), yielding compounds of Formula I wherein R⁷ is phenyl, substituted phenyl and five or six-membered ring heteroaryls such as furan, pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, or imidazole (path 2).

As illustrated in Scheme 10, compounds of Formula I prepared in Schemes 8 and 9 wherein R⁵ is a chlorine and R⁷ is not a chlorine can be further substituted by treatment with alkylboronic acids or esters under Suzuki reaction conditions (path 1), with sodium alkoxides (path 2), or with zinc cyanide (path 3) using conditions previously described to provide compounds of Formula I wherein R⁵ is alkyl, O(alkyl) or CN and R⁷ is as described above.

In Scheme 11, tertiary alcohols I can be treated with base, such as NaH, and alkylated with MeI in DMF to provide compounds of Formula I wherein R³ is OMe.

Synthetic routes to compounds of Formula I, wherein R³ is NH₂, are illustrated in Scheme 12. Ketimines XXXVI may be prepared by Ti(OEt)₄ mediated condensation of ketones XXVIII with 2-methylpropane-2-sulfinamide in refluxing THF. Addition of n-BuLi to the reaction mixture of ketimines XXXVI and 6-bromoquinolines VI at −78° C. followed by cleavage of the tert-butanesulfinyl group with HCl in MeOH liberates amines I.

As shown in Scheme 13, the quinolines of Formula I wherein R⁷ is —CN can be hydrolyzed as described in US20080188521 by treatment with sodium carbonate and hydrogen peroxide to provide compounds of Formula I wherein R⁷ is CONH₂ (path 1) or can be treated with a strong acid like HCl to convert —CN to a carboxylic acid (path 2). Once formed the acid XXXVII can be further coupled to substituted amines using appropriate coupling reagents such as EDCI or HATU in the presence of a base such as triethylamine or Hunig's base to provide compounds of Formula I wherein R⁷ is CONA¹A².

Synthesis of compounds of Formula I, wherein R⁷ is an aminoalkylaminomethylene or an aminoalkoxymethylene can be prepared from 2-methylquinolines as shown in Scheme 14. Bromination of 2-methylquinolines of Formula I can be accomplished with N-bromosuccinamide in acetic acid at elevated temperatures as described in WO2010151740, to provide the methylbromide intermediates XXXVIII. Nucleophilic displacement of the bromide under basic conditions using procedures known in the art could afford compounds of Formula I wherein R⁷ is —CH₂N(H)C₍₂₋₃₎alkylNA¹A² or —CH₂N(CH₃)C₍₂₋₃₎alkylNA¹A² (path 1) or CH₂OC₍₂₋₃₎alkylNA¹A² (path 2) and A¹ and A² are defined above.

Compounds of Formula I wherein R¹, R² or R⁶ are pyridyl can be treated with m-chloroperbenzoic acid in a chlorinated solvent at ambient to 40° C. to form the pyridyl-N-oxides of Formula I.

As shown in Scheme 15, compounds of the Formula I wherein R³ is H can be prepared by treating compounds of Formula I wherein R³ is OH with an acid such as trifluoracetic acid in a solvent such as dichloromethane at room temperature or with heating (WO2009091735).

EXAMPLES

Compounds of the present invention can be prepared by methods known to those who are skilled in the art. The following examples are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.

Intermediate 1 Step a 4-Chloro-N-methoxy-N-methylbenzamide

Pyridine (27.6 mL, 343 mmol) was added to N,O-dimethylhydroxylamine hydrochloride (16.7 g, 172 mmol) in DCM (400 mL). 4-Chlorobenzoyl chloride (20 mL, 156 mmol) was then added and the mixture was stirred at room temperature for 3 days. Solids were removed by vacuum filtration, washing with DCM. The filtrate was washed with 1 N aqueous HCl followed by water. The organic phase was dried (Na₂SO₄), filtered, and concentrated, affording the crude title compound as a colorless liquid which was used without purification in the next step.

Intermediate 1 Step b (4-Chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone

Ethyl magnesium bromide (3.0 M in diethyl ether, 21.5 mL, 64.4 mmol) was added via syringe over a few minutes to a clear colorless solution of 5-bromo-1-methyl-1H-imidazole (10.4 g, 64.4 mmol) in THF (100 mL) under a nitrogen atmosphere in an ice bath. A white precipitate formed during the addition. The mixture was removed from the ice bath and was stirred for 20 min, then was again cooled in an ice bath before addition of 4-chloro-N-methoxy-N-methylbenzamide (10.7 g, 53.6 mmol, Intermediate 1, step a). The resulting white suspension was stirred overnight at room temperature. The reaction was quenched by addition of saturated aqueous NH₄Cl and diluted with water. The mixture was partially concentrated to remove THF and was diluted with DCM. The mixture was acidified to pH 1 with 1 N aqueous HCl, then neutralized with saturated aqueous NaHCO₃. The phases were separated and the aqueous phase was further extracted with DCM. The organic extracts were washed with water, then were dried (Na₂SO₄), filtered, and concentrated, affording a white solid. The crude product was triturated with a mixture of EtOAc:heptanes (1:1, 150 mL). The precipitated solid was collected by vacuum filtration, washing with heptanes, to afford the title compound.

Intermediate 2 Step a 6-(Trifluoromethyl)nicotinoyl chloride

To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45.0 g, 236 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.8 mmol) via syringe. To this solution was added oxalyl chloride (24.5 mL, 283 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brownish semisolid.

Intermediate 2 Step b N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide

To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 125 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinoyl chloride (49.3 g, 235 mmol, Intermediate 2, step a), dichloromethane (493 mL), and N,O-dimethylhydroxylamine hydrochloride (25.63 g, 258.8 mmol). After the mixture was cooled to 7° C., diisopropylethylamine (90.26 mL, 517.6 mmol) was added such that the addition temperature did not exceed 16° C. After the addition, the reaction was allowed to warm to room temperature. The reaction was then transferred to a separatory funnel and the organic layer was washed with saturated NaHCO₃ (2×100 mL) followed by water (100 mL) and then dried over sodium sulfate and filtered. Solvent removal afforded a brownish oil as the title compound.

Intermediate 2 Step c (1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone

To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogen bubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96 g, 297.9 mmol), followed by THF (537 mL). To this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex (246.8 mL, 320.8 mmol, 1.3 M in THF) (addition temperature maintained between 16.6 and 25° C.) to afford a milky suspension and the reaction was stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. To this mixture was added a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14 mmol, Intermediate 2, step b) in THF (268.3 mL) (addition temperature between 5.3 and 5.6° C.) to afford an orange mixture. After addition, the reaction was warmed to room temperature over 2 hours. After stirring at room temperature for 18 hours, THF (200 mL) was added and the reaction was stirred for 2 hours. The reaction was then cooled to 4° C. with an ice bath and carefully quenched with 2 N aqueous HCl to pH=7, quenching temperature reached 12° C. The mixture was diluted with ethyl acetate (500 mL), phase separated and the organic layer was washed with brine (2×200 mL) and dried over sodium sulfate, filtered and the solvent was removed. Hot ether was added and then filtered to give the title compound as a solid.

Intermediate 3 Step a N-Methoxy-N-methylthiazole-5-carboxamide

Triethylamine (2.77 mL, 19.9 mmol) was added slowly to a mixture of commercially available thiazole-5-carboxylic acid (1.03 g, 7.98 mmol), N,O-dimethylhydroxylamine hydrochloride (0.778 g, 7.98 mmol), and EDCI (1.83 g, 9.57 mmol) in CH₂Cl₂ (10 mL). The mixture was stirred at room temperature for 72 hours then quenched with saturated aqueous NaHCO₃. Water (50 mL) was added followed by additional CH₂Cl₂. The mixture was stirred for 10 minutes and layers were separated. The CH₂Cl₂ layer was dried over Na₂SO₄ and filtered. The solvent was removed under reduced pressure and the residual oil was chromatographed (CH₂Cl₂/EtOAc) to provide the title compound as a white solid.

Intermediate 3 Step b (1-Methyl-1H-imidazol-5-yl)(thiazol-5-yl)methanone

To a solution of 5-bromo-1-methyl-1H-imidazole (1.14 g, 7.11 mmol) in DCM was added ethyl magnesium bromide (2.34 mL, 7.11 mmol; 3 M in diethyl ether) dropwise over a 10 minute period. The resulting pale yellow solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N-methylthiazole-5-carboxamide (Intermediate 3, step a) (1.02 g, 5.92 mmol) dissolved in DCM (3 mL) was added dropwise. The cold bath was removed and the reaction mixture stirred at room temperature for 48 hours. To the resulting yellow suspension was added water followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM, dried over Na₂SO₄, filtered and concentrated.

Et₂O was added and the mixture sonicated. The precipitates were collected by filtration and dried to provide the title compound as a tan solid.

Intermediate 4 Step a 6-Chloropyridine-3-carbonyl chloride

In a 250-mL round-bottom flask was placed a solution of 6-chloropyridine-3-carboxylic acid (15.8 g, 100 mmol) in thionyl chloride (100 mL). The resulting solution was heated at reflux for 5 hours and concentrated under vacuum to give the title compound as a yellow oil.

Intermediate 4 Step b 6-Chloro-N-methoxy-N-methylpyridine-3-carboxamide

To a 1000-mL round-bottom flask containing N,O-dimethylhydroxylamine hydrochloride (12.0 g, 123 mmol) and triethylamine (40.0 g, 395 mmol) was added a solution of 6-chloropyridine-3-carbonyl chloride (17.6 g, 100 mmol, Intermediate 4, step a) in dichloromethane (100 mL) dropwise. The resulting mixture was stirred for 12 hours at room temperature and filtered. The filtrate was concentrated under vacuum to give the title compound as a yellow oil.

Intermediate 4 Step c 2-Chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine

To a 250-mL 3-necked round-bottom flask containing a solution of 1-methyl-1H-imidazole (5.00 g, 60.9 mmol) and tetrahydrofuran (40 mL) was added n-BuLi (29.3 mL, 73.3 mmol, 2.5 M in hexanes) at −78° C., and stirred for 45 minutes. To this mixture Et₃SiCl (9.15 g, 61.0 mmol) was added, and stirring was continued for 1 hour at −78° C. To the mixture was added n-BuLi (26.0 mL, 65.0 mmol, 2.5 M in hexanes). After stirring for another 45 minutes, a solution of 6-chloro-N-methoxy-N-methylpyridine-3-carboxamide (8.13 g, 40.5 mmol, Intermediate 4, step b) in tetrahydrofuran (20 mL) was added at −78° C. The resulting mixture was allowed to warm up to room temperature overnight. To the mixture was added 1.0 M aqueous HCl until pH 3-4. After stirring for 2 hours at room temperature, the mixture was basified with 1.5 M aqueous sodium hydroxide until pH 9-10. The resulting mixture was diluted with 100 mL of H₂O and extracted with 3×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (100:0 to 15:1) to afford the title compound as a yellow solid.

Intermediate 4 Step d (6-Methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanone

In a 50-mL round-bottom flask was placed a solution of Na (260 mg, 11.3 mmol) in methanol (15 mL) and the solution was stirred for 30 minutes at room temperature. Then 2-chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine (250 mg, 1.13 mmol, Intermediate 4, step c) was added. The resulting mixture was stirred for 4 hours at 75° C. and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, 100:0-20:1 CH₂Cl₂:MeOH) to give the title compound as a light yellow solid.

Intermediate 5 Step a Methyl 5-bromo-2-(2-phenoxyacetamido)benzoate

To a solution of commercially available methyl 2-amino-5-bromobenzoate (10.0 g, 43.5 mmol) in dichloromethane (100 mL) was added 2-phenoxyacetyl chloride (6.60 mL, 47.8 mmol). The white suspension formed was cooled to 0° C. and treated with triethylamine (13.3 mL, 95.6 mmol) dropwise. The resulting solution was stirred at room temperature for 0.5 hours. The mixture was diluted with CH₂Cl₂ and was washed with water and saturated aqueous NH₄Cl solution. The organic phase was dried (MgSO₄), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 7% EtOAc-Heptane), affording the title compound.

Intermediate 5 Step b 6-Bromo-4-hydroxy-3-phenoxyquinolin-2(1H)-one

To a solution of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (7.28 g, 20.0 mmol, Intermediate 5, step a) in tetrahydrofuran (215 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 118.7 mL, 59.37 mmol) over 7 minutes. The mixture was stirred at −78° C. for 5 minutes and 0° C. for 1.5 hours. The resulting cold solution was quenched with water. The white solid formed was completely dissolved by addition of excess water. The aqueous phase was washed once with EtOAc and then acidified to pH>2 by slow addition of 2 N aqueous HCl solution. The off-white precipitate formed was filtered and dried in the air overnight and at 40° C. for 1 hour to provide the title compound.

Intermediate 5 Step c 6-Bromo-2,4-dichloro-3-phenoxyquinoline

To a suspension of 6-bromo-4-hydroxy-3-phenoxyquinolin-2(1H)-one (4.30 g, 13.0 mmol, Intermediate 5, step b) in CH₃CN (30 mL) was added phosphoryl trichloride (3.60 mL, 38.8 mmol). The resulting mixture was heated at 100° C. for 16 hours. The dark suspension was cooled to room temperature and filtered. The solid residue was washed with cold MeOH to provide an off-white solid. The filtrate was concentrated to one third of its volume, added small amount of MeOH and cooled to 0° C. to provide a second batch of solid suspension. This was filtered and the residue was washed with cold MeOH. The two batches of solid were combined and dried under vacuum to provide the title compound.

Intermediate 5 Step d 6-Bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine

A mixture of 6-bromo-2,4-dichloro-3-phenoxyquinoline (2.92 g, 7.91 mmol, Intermediate 5, step c), diethylamine (8.2 mL, 79.1 mmol) and DMF (2 mL) in a sealed tube was heated at 80° C. for 15 hours. The resulting solution was cooled to room temperature and diluted with EtOAc. The organic phase was washed thoroughly with water, dried (MgSO₄), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% EtOAc-Heptane), affording the title compound.

Intermediate 5 Step e 6-Bromo-4-chloro-N,N-dimethyl-3-phenoxyquinolin-2-amine

The title compound was prepared using dimethylamine in place of diethylamine according to the procedure described in Intermediate 5, step d.

Intermediate 6 Step a Methyl 5-bromo-2-(2-(4-fluorophenoxy)acetamido)benzoate

The title compound was prepared using commercially available 2-(4-fluorophenoxy)acetyl chloride in place of 2-phenoxyacetyl chloride according to the procedure described in Intermediate 5, step a.

Intermediate 6 Step b 6-Bromo-3-(4-fluorophenoxy)-4-hydroxyquinolin-2(1H)-one

The title compound was prepared using methyl 5-bromo-2-(2-(4-fluorophenoxy)acetamido)benzoate (Intermediate 6, step a) in place of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (Intermediate 5, step a) according to the procedure described in Intermediate 5, step b.

Intermediate 6 Step c 6-Bromo-2,4-dichloro-3-(4-fluorophenoxy)quinoline

The title compound was prepared using 6-bromo-3-(4-fluorophenoxy)-4-hydroxyquinolin-2(1H)-one (Intermediate 6, step b) in place of 6-bromo-4-hydroxy-3-phenoxyquinolin-2(1H)-one (Intermediate 5, step b) according to the procedure described in Intermediate 5, step c except the final solid was further purified by flash column chromatography (silica gel, 2% EtOAc: Heptane), affording the title compound.

Intermediate 6 Step d 6-Bromo-4-chloro-N,N-diethyl-3-(4-fluorophenoxy)quinolin-2-amine

The title compound was prepared using 6-bromo-2,4-dichloro-3-(4-fluorophenoxy)quinoline (Intermediate 6, step c) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure described in Intermediate 5, step d.

Intermediate 7 Step a 1-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroethanone

A solution of diisopropylamine (22.1 mL, 157 mmol) in 140 mL THF was stirred under argon at −68° C. while n-BuLi (57.9 mL, 2.59 M in hexane, 150 mmol) was added in a fine stream in 2 portions over 6 minutes. The resulting pale yellow homogeneous solution was removed from the acetone/dry ice bath and stirred at ambient conditions for 9 minutes, and was then cooled back down to −68° C. and a solution of 1-bromo-4-fluorobenzene (15.6 mL, 143 mmol) in THF (30 mL) was added dropwise over 5 minutes. The reaction was then stirred in the cold bath for another 6 minutes, and the pale yellow reaction was then treated dropwise with a solution of ethyl trifluoroacetate (18.7 mL, 157 mmol) in THF (30 mL) over ˜8 minutes (internal temp rose to −47° C.). The pale yellow reaction was then stirred overnight as the acetone/dry ice bath expired (15 hours). The resulting yellow homogeneous solution was washed with 5 M aqueous NH₄Cl (2×50 mL), and the organic layer was dried (Na₂SO₄), filtered, and concentrated to provide the crude title compound as a clear dark yellow oil.

Intermediate 7 Step b 1-(2-Amino-5-bromophenyl)-2,2,2-trifluoroethanone

A solution of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.67 g, 24.6 mmol, Intermediate 7, step a) in DMSO (6.2 mL) was treated with NaN₃ (1.76 g, 27.0 mmol) and stirred under air (lightly capped) at 95° C. for 1 hour. The brownish-red opaque reaction was then cooled to room temperature on an ice bath, diluted with EtOAc (49 mL), treated with SnCl₂.dihydrate (6.66 g, 29.5 mmol) in several portions over ˜30 seconds followed by water (1.33 mL, 73.8 mmol), and the mixture was stirred at room temperature for 30 minutes. The reddish solution with heavy off-white particulates was then treated with anhydrous Na₂SO₄ (˜6 g) and stirred vigorously for a few minutes. The mixture was then filtered over a bed of Celite®, and the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient to provide the title compound as an orange oil that crystallized upon standing.

Intermediate 7 Step c 6-Bromo-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-2(1H)-one

To a solution of 1-(2-amino-5-bromophenyl)-2,2,2-trifluoroethanone (2.76 g, 10.3 mmol, Intermediate 7, step b) in dichloromethane (20 mL) was added commercially available 2-(4-chlorophenoxy)acetyl chloride (2.11 g, 10.3 mmol). The resulting white solution was cooled with an ice bath to 0° C. and treated with triethylamine (4.29 mL, 30.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 12 hours and at 60° C. for 2 hours. The mixture was diluted with dichloromethane at room temperature and washed with water. The organic phase was dried (MgSO₄), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 25% EtOAc-Heptane), affording the title compound.

Intermediate 7 Step d 6-Bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline

To a suspension of 6-bromo-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-2(1H)-one (1.08 g, 2.58 mmol, Intermediate 7, step c) in phosphoryl trichloride (7.2 mL, 77.3 mmol) was added diisopropylethylamine (1.33 mL, 7.74 mmol). The resulting mixture was heated at 120° C. for 8 hours. The solution was concentrated in vacuo at room temperature and the resulting residue was cooled to 0° C. with an ice bath. To the cold residue was added ice in small portions to quench excess phosphoryl trichloride. After cessation of bubbling, the solid suspension was diluted with dichloromethane. The organic phase was separated out, dried (MgSO₄), filtered and concentrated to yield the title compound.

Intermediate 7 Step e 6-Bromo-3-(4-chlorophenoxy)-N,N-diethyl-4-(trifluoromethyl)quinolin-2-amine

The title compound was prepared using 6-bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline (Intermediate 7, step d) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure described in Intermediate 5, step d except the reaction mixture was heated at 60° C. under reflux condenser for 12 hours.

Intermediate 7 Step f 6-Bromo-3-(4-chlorophenoxy)-2-ethoxy-4-(trifluoromethyl)quinoline

The title compound was prepared using 6-bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline (Intermediate 7, step d) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 2 except only one equivalent of sodium ethoxide was used.

Intermediate 8 Step a 6-Bromo-3-phenoxy-4-(trifluoromethyl)quinolin-2(1H)-one

The title compound was prepared using commercially available 2-phenoxyacetyl chloride in place of 2-(4-chlorophenoxy)acetyl chloride according to the procedure described in Intermediate 7, step c.

Intermediate 8 Step b 6-Bromo-2-chloro-3-phenoxy-4-(trifluoromethyl)quinoline

The title compound was prepared using 6-bromo-3-phenoxy-4-(trifluoromethyl)quinolin-2(1H)-one (Intermediate 8, step a) in place of 6-bromo-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-2(1H)-one (Intermediate 7, step c) according to the procedure described in Intermediate 7, step d.

Intermediate 8 Step c 6-Bromo-N,N-diethyl-3-phenoxy-4-(trifluoromethyl)quinolin-2-amine

The title compound was prepared using 6-bromo-2-chloro-3-phenoxy-4-(trifluoromethyl)quinoline (Intermediate 8, step b) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure described in Intermediate 5, step d except the reaction mixture was heated at 100° C. under reflux condenser for 2.5 hours.

Intermediate 9 Step a Methyl 5-bromo-2-(2-(4-chlorophenoxy)acetamido)benzoate

The title compound was prepared using commercially available 2-(4-chlorophenoxy)acetyl chloride in place of 2-phenoxyacetyl chloride according to the procedure described in Intermediate 5, step a.

Intermediate 9 Step b 6-Bromo-3-(4-chlorophenoxy)-4-hydroxyquinolin-2(1H)-one

The title compound was prepared using methyl 5-bromo-2-(2-(4-chlorophenoxy)acetamido)benzoate (Intermediate 9, step a) in place of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (Intermediate 5, step a) according to the procedure described in Intermediate 5, step b.

Intermediate 9 Step c 6-Bromo-2,4-dichloro-3-(4-chlorophenoxy)quinoline

The title compound was prepared using 6-bromo-3-(4-chlorophenoxy)-4-hydroxyquinolin-2(1H)-one (Intermediate 9, step b) in place of 6-bromo-4-hydroxy-3-phenoxyquinolin-2(1H)-one (Intermediate 5, step b) according to the procedure described in Intermediate 5, step c.

Intermediate 9 Step d 2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-chlorophenoxy)quinoline

The title compound was prepared using 6-bromo-2,4-dichloro-3-(4-chlorophenoxy)quinoline (Intermediate 9, step c) and azetidine (1.1 equivalent) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) and diethylamine, respectively, according to the procedure described in Intermediate 5, step d.

Intermediate 10 Step a 2-(4-Cyanophenoxy)acetyl chloride

To a suspension of commercially available 2-(4-cyanophenoxy)acetic acid (4.0 g, 22.6 mmol) in dichloromethane (80 mL) was added oxalyl dichloride (2.17 mL, 24.8 mmol). To this mixture was added N,N-dimethylformamide (30 μL) dropwise and stirred for 2 hours during which cessation of evolution of gas was observed. The resulting solution was diluted with dichloromethane (50 mL) and the solvent was removed under reduced pressure to provide the title compound as an oil which became a solid upon storing in the refrigerator.

Intermediate 10 Step b Methyl 5-bromo-2-(2-(4-cyanophenoxy)acetamido)benzoate

The title compound was prepared using 2-(4-cyanophenoxy)acetyl chloride (Intermediate 10, step a) in place of 2-phenoxyacetyl chloride according to the procedure described in Intermediate 5, step a.

Intermediate 10 Step c 4-((6-Bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)oxy)benzonitrile

The title compound was prepared using methyl 5-bromo-2-(2-(4-cyanophenoxy)acetamido)benzoate (Intermediate 10, step b) in place of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (Intermediate 5, step a) according to the procedure described in Intermediate 5, step b.

Intermediate 10 Step d 4-((6-Bromo-2,4-dichloroquinolin-3-yl)oxy)benzonitrile

The title compound was prepared using 4-((6-bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)oxy)benzonitrile (Intermediate 10, step c) in place of 6-bromo-4-hydroxy-3-phenoxyquinolin-2(1H)-one (Intermediate 5, step b) according to the procedure described in Intermediate 5, step c.

Intermediate 10 Step e 4-((2-(Azetidin-1-yl)-6-bromo-4-chloroquinolin-3-yl)oxy)benzonitrile

The title compound was prepared using 4-((6-bromo-2,4-dichloroquinolin-3-yl)oxy)benzonitrile (Intermediate 10, step d) and azetidine (1.1 equivalent) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) and diethyl amine, respectively, according to the procedure described in Intermediate 5, step d.

Intermediate 10 Step f 4-((6-Bromo-4-chloro-2-(pyrrolidin-1-yl)quinolin-3-yl)oxy)benzonitrile

The title compound was prepared using 4-((6-bromo-2,4-dichloroquinolin-3-yl)oxy)benzonitrile (Intermediate 10, step d) and pyrrolidine (3 equivalent) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) and diethylamine, respectively, according to the procedure described in Intermediate 5, step d.

Intermediate 11 Step a 6-Bromo-4-hydroxyquinolin-2(1H)-one

According to the general method described in Synth. Commun. 2010, 40, 732, a mixture of 4-bromoaniline (10.0 g, 58.1 mmol) and 2,2-dimethyl-1,3-dioxan-4,6-dione (8.40 g, 58.1 mmol) was heated at 80° C. for 1 hour and cooled to room temperature to provide 3-((4-bromophenyl)amino)-3-oxopropanoic acid as a solid. A stream of nitrogen gas was passed over the solid product to remove liquid acetone formed as a by-product. To this solid was added Eaton's reagent (40 mL) and heated at 70° C. for 12 hours and cooled to room temperature. To the resulting mixture was added water and stirred vigorously to provide a suspension which was filtered. The solid residue was washed with water and dried in air to provide the title compound.

Intermediate 11 Step b (6-Bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)(phenyl)iodoniumtrifluoromethane sulfonate

To a suspension of 6-bromo-4-hydroxyquinolin-2(1H)-one (11.0 g, 45.8 mmol, Intermediate 11, step a) and (diacetoxyiodo)benzene (13.4 g, 41.7 mmol) in dichloromethane (180 mL) at 0° C. was added trifluoromethanesulfonic acid (4.06 mL, 45.8 mmol) dropwise. The resulting mixture was stirred in an ice-bath for 1 hour and at room temperature for 2 hours to provide a suspension which was filtered. The solid product was washed with dichloromethane and dried under vacuum at 50° C. for 12 hours to yield the title compound.

Intermediate 11 Step c 6-Bromo-4-hydroxy-3-(phenylamino)quinolin-2(1H)-one

A mixture of (6-bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)(phenyl) iodoniumtrifluoromethane sulfonate (1.40 g, 2.36 mmol, Intermediate 11, step b) and aniline (1 mL) was stirred for 4 hours at room temperature. To this was added DCM and the resulting suspension was filtered. The solid was washed first with DCM followed by water and dried in the air and under vacuum at 50° C. to yield the title compound.

Intermediate 11 Step d 6-Bromo-2,4-dichloro-N-phenylquinolin-3-amine

To 6-bromo-4-hydroxy-3-(phenylamino)quinolin-2(1H)-one (648 mg, 1.96 mmol, Intermediate 11, step c) was added phosphoryl trichloride (5 mL) and heated at 100° C. for 24 hours. The resulting solution was concentrated in vacuo to remove excess phosphoryl trichloride and the thick liquid remained was cooled to 4° C. and treated with aqueous ammonium hydroxide (28-30%) dropwise to bring to pH 9-10. To this was added water, heated at 40° C. for 0.5 hour and the suspension formed was filtered. The solid, the title compound as phosphoryl amide adduct, was suspended in water, acidified with conc. HCl to pH=2 and heated at 50° C. overnight and 90° C. for 3 hours. The resulting mixture was cooled to room temperature, basified with 3 N aqueous NaOH solution and extracted with EtOAc. The organic phase was separated, dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10% EtOAc-Heptane), affording the title compound.

Intermediate 11 Step e tert-Butyl (6-bromo-2,4-dichloroquinolin-3-yl)(phenyl)carbamate

To a solution of 6-bromo-2,4-dichloro-N-phenylquinolin-3-amine (226 mg, 0.610 mmol, Intermediate 11, step d) in tetrahydrofuran (6 mL) was added di-tert-butyl dicarbonate (214 mg, 0.980 mmol), N,N-dimethylpyridin-4-amine (120 mg, 0.980 mmol) and stirred overnight at room temperature. The resulting solution was diluted with EtOAc and the organic phase was washed with saturated sodium bicarbonate solution followed by brine. The organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 3% EtOAc-Heptane), affording the title compound.

Intermediate 11 Step f 6-Bromo-4-hydroxy-3-(methyl(phenyl)amino)quinolin-2(1H)-one

The title compound was prepared using N-methylaniline in place of aniline according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.

Intermediate 11 Step g 6-Bromo-3-(ethyl(phenyl)amino)-4-hydroxyquinolin-2(1H)-one

The title compound was prepared using N-ethylaniline in place of aniline according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.

Intermediate 11 Step h 6-Bromo-4-hydroxy-3-(isopropyl(phenyl)amino)quinolin-2(1H)-one

The title compound was prepared using N-isopropylaniline at 50° C. in place of aniline at room temperature according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.

Intermediate 11 Step i 6-Bromo-2,4-dichloro-N-methyl-N-phenylquinolin-3-amine

To 6-bromo-4-hydroxy-3-(methyl(phenyl)amino)quinolin-2(1H)-one (180 mg, 0.520 mmol, Intermediate 11, step f) was added phosphoryl trichloride (1 mL) and heated at 100° C. for 12 hours. The resulting solution was concentrated in vacuo to remove excess phosphoryl trichloride and the thick liquid remained was cooled to 4° C. and treated with aqueous ammonium hydroxide (28-30%) dropwise to bring pH 9-10. To this was added DCM and the organic phase was washed with water, dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 3% EtOAc-Heptane), affording the title compound.

Intermediate 11 Step j 6-Bromo-2,4-dichloro-N-ethyl-N-phenylquinolin-3-amine

The title compound was prepared using 6-bromo-3-(ethyl(phenyl)amino)-4-hydroxyquinolin-2(1H)-one (Intermediate 11, step g) in place of 6-bromo-4-hydroxy-3-(methyl(phenyl)amino)quinolin-2(1H)-one according to the procedure of Intermediate 11, step i to afford the title compound.

Intermediate 11 Step k 6-Bromo-2,4-dichloro-N-isopropyl-N-phenylquinolin-3-amine

The title compound was prepared using 6-bromo-4-hydroxy-3-(isopropyl(phenyl)amino)quinolin-2(1H)-one (Intermediate 11, step h) in place of 6-bromo-4-hydroxy-3-(methyl(phenyl)amino)quinolin-2(1H)-one according to the procedure of Intermediate 11, step i to afford the title compound.

Intermediate 11 Step 1 tert-Butyl (6-bromo-4-chloro-2-(diethylamino)quinolin-3-yl)(phenyl)carbamate

A mixture of tert-butyl (6-bromo-2,4-dichloroquinolin-3-yl)(phenyl)carbamate (120 mg, 0.256 mmol, Intermediate 11, step e), diethylamine (4.0 mL, 38.5 mmol) and DMF (1 mL) in a sealed tube was heated at 120° C. for 12 hours. The resulting solution was cooled to room temperature and diluted with EtOAc. The organic phase was washed thoroughly with water, dried (MgSO₄), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% EtOAc-Heptane), affording the title compound.

Example 1 (4-Chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol

To a solution of 6-bromo-2,4-dichloro-3-phenoxyquinoline (500 mg, 1.36 mmol, Intermediate 5, step c) in tetrahydrofuran (14 mL) at −78° C. was added n-butyllithium (1.6 M solution in hexanes, 1.3 mL, 2.03 mmol) dropwise and stirred at this temperature for 5 minutes. To the resulting dark red solution was added (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (448 mg, 2.0 mmol, Intermediate 1, step b) and stirred in an ice bath (0° C.) for 0.5 hour. The yellow-orange solution was quenched with water and diluted with EtOAc. The separated organic phase was dried (MgSO₄), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% MeOH-DCM), affording the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (br. s., 1H), 8.21 (s, 1H), 8.13 (d, J=8.80 Hz, 1H), 7.80 (d, J=8.80 Hz, 1H), 7.73 (br. s., 1H), 7.51 (d, J=8.31 Hz, 2H), 7.42 (d, J=8.31 Hz, 2H), 7.37 (t, J=7.70 Hz, 2H), 7.09-7.17 (m, 1H), 7.02 (br. s., 1H), 6.97 (d, J=8.56 Hz, 2H), 3.54 (s, 3H); MS m/e 511.8 [M+H]⁺.

Example 2a (4-Chloro-2-ethoxy-3-phenoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

To a solution of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (15 mg, 0.024 mmol, Example 1) in ethanol (0.25 mL) was added sodium ethoxide (0.016 mL, 0.048 mmol, 21 wt. % solution in ethanol). The mixture was heated at 60° C. for 12 hours and concentrated. The residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.08 (d, J=2.02 Hz, 1H), 7.89 (d, J=8.59 Hz, 1H), 7.61 (dd, J=2.02, 8.59 Hz, 2H), 7.50 (d, J=8.59 Hz, 2H), 7.40 (d, J=8.59 Hz, 2H), 7.33 (t, J=8.08 Hz, 2H), 7.09 (t, J=7.33 Hz, 1H), 6.98 (d, J=1.01 Hz, 1H), 6.90 (d, J=8.08 Hz, 2H), 4.45 (q, J=7.07 Hz, 2H), 3.55 (s, 3H), 1.17 (t, J=7.07 Hz, 3H)); MS m/e 521.1 [M+H]⁺.

Example 2a was purified by chiral HPLC (Daicel Chiralpak AD, 10% EtOH-Heptane) to give two enantiomers. The first eluting enantiomer was Example 2b and the second eluting enantiomer was Example 2c.

Example 2b

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=2.02 Hz, 1H), 7.84 (d, J=8.59 Hz, 1H), 7.69 (s, 1H), 7.58 (dd, J=2.02, 8.59 Hz, 1H), 7.43 (d, J=9.09 Hz, 2H), 7.29-7.36 (m, 4H), 7.05-7.11 (m, 2H), 6.91 (d, J=8.08 Hz, 2H), 6.17 (d, J=1.01 Hz, 1H), 4.44 (q, J=7.07 Hz, 2H), 3.55 (s, 3H), 1.17 (t, J=7.07 Hz, 3H); MS m/e 521.1 [M+H]⁺.

Example 2c

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=2.02 Hz, 1H), 7.84 (d, J=8.59 Hz, 1H), 7.69 (s, 1H), 7.58 (dd, J=2.02, 9.09 Hz, 1H), 7.43 (d, J=8.59 Hz, 2H), 7.28-7.36 (m, 4H), 7.05-7.11 (m, 2H), 6.91 (d, J=7.58 Hz, 2H), 6.17 (s, 1H), 4.44 (q, J=6.74 Hz, 2H), 3.55 (s, 3H), 1.17 (t, J=7.07 Hz, 3H); MS m/e 521.1 [M+H]⁺.

Example 3a (4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

To a solution of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (525 mg, 1.29 mmol, Intermediate 5, step d) in tetrahydrofuran (12 mL) at −78° C. was added n-butyllithium (1.6 M solution in hexanes, 1.2 mL, 1.94 mmol) dropwise over 1 minute and stirred at this temperature for 5 minutes. To the resulting dark red solution was added (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (428 mg, 1.94 mmol, Intermediate 1, step b) and stirred in an ice bath (0° C.) for 0.5 hours. The yellow-orange solution was quenched with water and diluted with EtOAc. The organic phase was separated, dried (MgSO₄), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% MeOH-DCM), affording the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (d, J=2.02 Hz, 1H), 7.64-7.70 (m, 2H), 7.46 (dd, J=2.02, 9.09 Hz, 1H), 7.42 (d, J=9.09 Hz, 2H), 7.29-7.35 (m, 4H), 7.06 (t, J=7.33 Hz, 1H), 6.98 (s, 1H), 6.80 (d, J=7.58 Hz, 2H), 6.16 (d, J=1.01 Hz, 1H), 3.51 (q, J=7.07 Hz, 4H), 3.34 (br. s., 3H), 1.05 (t, J=7.07 Hz, 6H)); MS m/e 548.8 [M+H]⁺.

Example 3a was purified by chiral HPLC (Daicel Chiralpak AD, 10% EtOH-MeOH) to give two enantiomers. The first eluting enantiomer was Example 3b and the second eluting enantiomer was Example 3c.

Example 3b

¹H NMR (600 MHz, DMSO-d₆) δ 7.89 (d, J=2.20 Hz, 1H), 7.69 (br. s., 1H), 7.68 (d, J=8.80 Hz, 1H), 7.49 (dd, J=2.02, 8.62 Hz, 1H), 7.42 (d, J=8.44 Hz, 2H), 7.30-7.36 (m, 4H), 7.07 (t, J=7.34 Hz, 1H), 6.90 (s, 1H), 6.81 (d, J=8.07 Hz, 2H), 6.21 (s, 1H), 3.54 (q, J=6.97 Hz, 4H), 3.36 (s, 3H), 1.07 (t, J=6.97 Hz, 6H); MS m/e 548.8 [M+H]⁺.

Example 3c

¹H NMR (600 MHz, DMSO-d₆) δ 7.89 (d, J=1.10 Hz, 1H), 7.73 (br. s., 1H), 7.68 (d, J=8.80 Hz, 1H), 7.49 (dd, J=1.83, 8.80 Hz, 1H), 7.42 (d, J=8.44 Hz, 2H), 7.30-7.36 (m, 4H), 7.07 (t, J=7.34 Hz, 1H), 6.91 (s, 1H), 6.81 (d, J=8.07 Hz, 2H), 6.23 (s, 1H), 3.54 (q, J=6.97 Hz, 4H), 3.37 (s, 3H), 1.07 (t, J=6.97 Hz, 6H); MS m/e 548.8 [M+H]⁺.

Example 4 (2,4-Dichloro-3-phenoxyquinolin-6-yl)(6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared using (6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 4, step d) in place of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J=2.02 Hz, 1H), 8.08 (d, J=9.09 Hz, 1H), 7.99 (d, J=2.53 Hz, 1H), 7.76 (dd, J=2.02, 8.59 Hz, 1H), 7.71 (s, 1H), 7.65 (dd, J=2.53, 8.59 Hz, 1H), 7.35 (dd, J=7.58, 8.59 Hz, 2H), 7.22 (s, 1H), 7.12 (t, J=7.33 Hz, 1H), 6.99 (d, J=8.08 Hz, 2H), 6.83 (d, J=9.09 Hz, 1H), 6.22 (d, J=1.01 Hz, 1H), 3.84 (s, 3H), 3.36 (s, 3H); MS m/e 507.9 [M+H]⁺.

Example 5a (4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared using (6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 4, step d) in place of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 3a. ¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (d, J=2.02 Hz, 1H), 7.89 (d, J=2.02 Hz, 1H), 7.65-7.70 (m, 2H), 7.61 (dd, J=2.53, 8.59 Hz, 1H), 7.46 (dd, J=2.02, 8.59 Hz, 1H), 7.32 (t, J=7.83 Hz, 2H), 7.06 (t, J=7.07 Hz, 1H), 6.96 (s, 1H), 6.77-6.85 (m, 3H), 6.18 (s, 1H), 3.83 (s, 3H), 3.52 (q, J=6.91 Hz, 4H), 3.35 (s, 3H), 1.06 (t, J=6.82 Hz, 6H); MS m/e 545.0 [M+H]⁺.

Example 5a was purified by chiral HPLC (Daicel Chiralpak AD, 100% EtOH) to give two enantiomers. The first eluting enantiomer was Example 5b and the second eluting enantiomer was Example 5c.

Example 5b

¹H NMR (600 MHz, DMSO-d₆,45° C.) δ 7.99 (d, J=2.02 Hz, 1H), 7.90 (d, J=1.83 Hz, 1H), 7.69 (d, J=8.80 Hz, 2H), 7.62 (dd, J=2.75, 8.62 Hz, 1H), 7.49 (dd, J=1.83, 8.80 Hz, 1H), 7.33 (t, J=7.89 Hz, 2H), 7.07 (t, J=7.34 Hz, 1H), 6.90 (s, 1H), 6.78-6.84 (m, 3H), 6.23 (br. s., 1H), 3.85 (s, 3H), 3.54 (q, J=6.97 Hz, 4H), 3.39 (s, 3H), 1.07 (t, J=6.97 Hz, 6H); MS m/e 545.0 [M+H]⁺.

Example 5c

¹H NMR (600 MHz, DMSO-d₆,45° C.) δ 7.99 (d, J=2.02 Hz, 1H), 7.89 (d, J=2.20 Hz, 1H), 7.65-7.72 (m, 2H), 7.62 (dd, J=2.57, 8.80 Hz, 1H), 7.49 (dd, J=2.02, 8.99 Hz, 1H), 7.33 (t, J=8.07 Hz, 2H), 7.07 (t, J=7.34 Hz, 1H), 6.88 (s, 1H), 6.78-6.84 (m, 3H), 6.21 (br. s., 1H), 3.85 (s, 3H), 3.54 (q, J=6.97 Hz, 4H), 3.38 (s, 3H), 1.07 (t, J=6.97 Hz, 6H); MS m/e 545.0 [M+H]⁺.

Example 6a (4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) in place of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 3a. ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (d, J=1.52 Hz, 1H), 7.92-7.97 (m, 2H), 7.89-7.92 (m, 1H), 7.73 (s, 1H), 7.70 (d, J=8.59 Hz, 1H), 7.48 (dd, J=2.02, 8.59 Hz, 1H), 7.36 (s, 1H), 7.29-7.35 (m, 2H), 7.06 (t, J=7.58 Hz, 1H), 6.81 (d, J=8.08 Hz, 2H), 6.24 (s, 1H), 3.52 (q, J=7.07 Hz, 4H), 3.35 (br. s., 3H), 1.06 (t, J=7.07 Hz, 6H); MS m/e 582.9 [M+H]⁺.

Example 6a was purified by chiral HPLC (Daicel Chiralpak OD, 10% EtOH-Heptane) to give two enantiomers. The first eluting enantiomer was Example 6b and the second eluting enantiomer was Example 6c.

Example 6b

¹H NMR (400 MHz, MeOH-d₄) δ 8.77 (d, J=2.02 Hz, 1H), 7.99 (dd, J=2.02, 8.59 Hz, 1H), 7.94 (d, J=2.02 Hz, 1H), 7.82 (d, J=8.59 Hz, 1H), 7.75 (d, J=8.59 Hz, 1H), 7.73 (br. s., 1H), 7.55 (dd, J=2.02, 8.59 Hz, 1H), 7.28 (dd, J=7.58, 8.59 Hz, 2H), 7.00-7.07 (m, 1H), 6.75 (d, J=7.58 Hz, 2H), 6.34 (br. s., 1H), 3.60 (q, J=7.07 Hz, 4H), 3.49 (s, 3H), 1.11 (t, J=7.07 Hz, 6H); MS m/e 583.2 [M+H]⁺.

Example 6c

¹H NMR (400 MHz, MeOH-d₄) δ 8.77 (d, J=2.02 Hz, 1H), 7.99 (dd, J=2.02, 8.08 Hz, 1H), 7.94 (d, J=2.02 Hz, 1H), 7.82 (d, J=8.08 Hz, 1H), 7.71-7.77 (m, 2H), 7.55 (dd, J=2.02, 8.59 Hz, 1H), 7.24-7.31 (m, 2H), 7.00-7.07 (m, 1H), 6.75 (d, J=8.08 Hz, 2H), 6.34 (br. s., 1H), 3.60 (q, J=7.07 Hz, 4H), 3.49 (s, 3H), 1.11 (t, J=6.82 Hz, 6H); MS m/e 583.2 [M+H]⁺.

Example 7 (4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(3-chlorophenyl)(pyridin-3-yl)methanol

The title compound was prepared using (3-chlorophenyl)(pyridin-3-yl)methanone in place of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 3a, except the crude residue was purified by flash column chromatography (silica gel) in 30% EtOAc-Heptane. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49-8.53 (m, 1H), 8.48 (d, J=2.02 Hz, 1H), 7.80 (d, J=1.52 Hz, 1H), 7.68 (d, J=8.59 Hz, 1H), 7.63-7.66 (m, 1H), 7.47 (dd, J=2.02, 9.09 Hz, 1H), 7.36-7.42 (m, 4H), 7.28-7.35 (m, 2H), 7.18 (td, J=2.02, 4.29 Hz, 1H), 7.03-7.09 (m, 2H), 6.79 (d, J=8.08 Hz, 2H), 3.52 (q, J=7.07 Hz, 4H), 1.05 (t, J=6.82 Hz, 6H); MS m/e 545.0 [M+H]⁺.

Example 8 (4-Chloro-2-(diethylamino)-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(thiazol-5-yl)methanol.TFA

The title compound was prepared using (1-methyl-1H-imidazol-5-yl)(thiazol-5-yl)methanone (Intermediate 3, step b) in place of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 3 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. ¹H NMR (400 MHz, MeOH-d₄) δ 9.19 (br. s., 1H), 8.98 (s, 1H), 8.10 (d, J=2.02 Hz, 1H), 7.84 (d, J=9.09 Hz, 1H), 7.72 (br. s., 1H), 7.64 (dd, J=2.02, 8.59 Hz, 1H), 7.30 (t, J=8.08 Hz, 2H), 7.19 (s, 1H), 7.06 (t, J=7.58 Hz, 1H), 6.79 (d, J=8.08 Hz, 2H), 3.71 (s, 3H), 3.65 (q, J=7.07 Hz, 4H), 1.15 (t, J=7.07 Hz, 6H); MS m/e 521.0 [M+H]⁺.

Example 9a (4-Chloro-2-(diethylamino)-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl))(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using 6-bromo-4-chloro-N,N-diethyl-3-(4-fluorophenoxy)quinolin-2-amine (Intermediate 6, step d) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of Example 3 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (d, J=1.71 Hz, 1H), 7.95 (dd, J=2.20, 8.07 Hz, 1H), 7.92 (d, J=1.96 Hz, 1H), 7.89-7.91 (m, 1H), 7.73 (d, J=0.49 Hz, 1H), 7.70 (d, J=8.80 Hz, 1H), 7.49 (dd, J=1.96, 8.80 Hz, 1H), 7.34 (s, 1H), 7.14 (t, J=8.80 Hz, 2H), 6.85 (dd, J=4.40, 9.29 Hz, 2H), 6.24 (d, J=0.98 Hz, 1H), 3.52 (q, J=7.09 Hz, 4H), 3.35 (s, 3H), 1.06 (t, J=6.97 Hz, 6H); MS m/e 600.9 [M+H]⁺.

Example 9a was purified by chiral HPLC (Daicel Chiralpak AD, 10% EtOH-Heptane) to give two enantiomers. The first eluting enantiomer was Example 9b and the second eluting enantiomer was Example 9c.

Example 9b

¹H NMR (400 MHz, MeOH-d₄) δ 8.76 (d, J=2.02 Hz, 1H), 8.00 (dd, J=2.02, 8.08 Hz, 1H), 7.95 (d, J=2.02 Hz, 1H), 7.83 (d, J=8.08 Hz, 1H), 7.75 (d, J=9.09 Hz, 1H), 7.73 (s, 1H), 7.55 (dd, J=2.27, 8.84 Hz, 1H), 6.99-7.06 (m, 2H), 6.76 (dd, J=4.29, 9.35 Hz, 2H), 6.34 (d, J=1.01 Hz, 1H), 3.59 (q, J=6.74 Hz, 4H), 3.48 (s, 3H), 1.12 (t, J=7.07 Hz, 6H); MS m/e 601.2 [M+H]⁺.

Example 9c

¹H NMR (400 MHz, MeOH-d₄) δ 8.76 (d, J=2.02 Hz, 1H), 8.00 (dd, J=2.02, 8.08 Hz, 1H), 7.95 (d, J=2.02 Hz, 1H), 7.82 (d, J=8.59 Hz, 1H), 7.75 (d, J=8.59 Hz, 1H), 7.73 (s, 1H), 7.55 (dd, J=2.27, 8.84 Hz, 1H), 7.02 (t, J=8.59 Hz, 2H), 6.76 (dd, J=4.04, 9.09 Hz, 2H), 6.34 (d, J=1.01 Hz, 1H), 3.59 (q, J=7.07 Hz, 4H), 3.48 (s, 3H), 1.12 (t, J=7.07 Hz, 6H); MS m/e 601.2 [M+H]⁺.

Example 10a (4-Chloro-2-ethoxy-3-phenoxyquinolin-6-yl)(6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

The title compound was prepared using (2,4-dichloro-3-phenoxyquinolin-6-yl)(6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 4) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 2a except only one equivalent of sodium ethoxide was used. ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.08 (dd, J=2.27, 17.94 Hz, 2H), 7.90 (d, J=9.09 Hz, 1H), 7.70 (dd, J=2.53, 9.09 Hz, 1H), 7.61 (dd, J=2.02, 8.59 Hz, 2H), 7.33 (t, J=7.83 Hz, 2H), 7.09 (t, J=7.33 Hz, 1H), 7.04 (br. s., 1H), 6.92 (s, 1H), 6.87-6.91 (m, 2H), 4.45 (q, J=7.07 Hz, 2H), 3.86 (s, 3H), 3.58 (br. s., 3H), 1.18 (t, J=7.07 Hz, 3H); MS m/e 518.2 [M+H]⁺.

Example 10a was purified by chiral HPLC (Daicel Chiralpak AD, 50% EtOH-MeOH) to give two enantiomers. The first eluting enantiomer was Example 10b and the second eluting enantiomer was Example 10c.

Example 10b

¹H NMR (400 MHz, MeOH-d₄) δ 8.09 (d, J=1.96 Hz, 1H), 8.02 (d, J=2.20 Hz, 1H), 7.86 (d, J=8.80 Hz, 1H), 7.66-7.74 (m, 2H), 7.64 (dd, J=2.20, 8.80 Hz, 1H), 7.29 (dd, J=7.34, 8.80 Hz, 2H), 7.05 (t, J=7.34 Hz, 1H), 6.79-6.87 (m, 3H), 6.32 (br. s., 1H), 4.46 (q, J=7.09 Hz, 2H), 3.91 (s, 3H), 3.49 (s, 3H), 1.22 (t, J=7.09 Hz, 3H); MS m/e 518.2 [M+H]⁺.

Example 10c

¹H NMR (400 MHz, MeOH-d₄) δ 8.09 (d, J=1.71 Hz, 1H), 8.02 (d, J=2.20 Hz, 1H), 7.86 (d, J=8.56 Hz, 1H), 7.66-7.77 (m, 2H), 7.64 (dd, J=2.08, 8.68 Hz, 1H), 7.29 (dd, J=7.58, 8.56 Hz, 2H), 7.05 (t, J=7.34 Hz, 1H), 6.77-6.88 (m, 3H), 6.32 (br. s., 1H), 4.46 (q, J=7.09 Hz, 2H), 3.91 (s, 3H), 3.49 (s, 3H), 1.22 (t, J=7.09 Hz, 3H); MS m/e 518.2 [M+H]⁺.

Example 11 (2,4-Dichloro-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using 6-bromo-2,4-dichloro-3-(4-fluorophenoxy)quinoline (Intermediate 6, step c) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of Example 1 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 8.80 (d, J=2.02 Hz, 1H), 8.30 (d, J=2.02 Hz, 1H), 8.01-8.10 (m, 2H), 7.81-7.88 (m, 2H), 7.76 (s, 1H), 7.02-7.11 (m, 2H), 6.90 (dd, J=4.29, 9.35 Hz, 2H), 6.40 (s, 1H), 3.48 (s, 3H); MS m/e 564.9 [M+H]⁺.

Example 12 (4-Chlorophenyl)(2,4-dichloro-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared using 6-bromo-2,4-dichloro-3-(4-fluorophenoxy)quinoline (Intermediate 6, step c) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure of Example 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (d, J=2.02 Hz, 1H), 8.07 (d, J=9.09 Hz, 1H), 7.76 (dd, J=2.02, 8.59 Hz, 1H), 7.71 (s, 1H), 7.45 (d, J=9.09 Hz, 2H), 7.32-7.38 (d, J=8.59 Hz, 2H), 7.23 (s, 1H), 7.14-7.21 (m, 2H), 7.02-7.08 (m, 1H), 6.19 (d, J=1.01 Hz, 1H), 3.48 (s, 3H); MS m/e 529.8 [M+H]⁺.

Example 13 (2,4-Dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) in place of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (d, J=1.52 Hz, 1H), 8.22 (d, J=2.02 Hz, 1H), 8.10 (d, J=9.09 Hz, 1H), 8.01 (dd, J=2.02, 8.08 Hz, 1H), 7.93 (d, J=8.59 Hz, 1H), 7.79 (dd, J=2.02, 8.59 Hz, 1H), 7.76 (s, 1H), 7.60 (s, 1H), 7.32-7.40 (m, 2H), 7.12 (t, J=8.59 Hz, 1H), 6.99 (d, J=8.08 Hz, 2H), 6.29 (s, 1H), 3.35 (s, 3H); MS m/e 547.0 [M+H]⁺.

Example 14a (4-Chloro-2-ethoxy-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using (2,4-dichloro-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (Example 11) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 2a except only one equivalent of sodium ethoxide was used. ¹H NMR (400 MHz, MeOH-d₄) δ 8.78 (d, J=1.96 Hz, 1H), 8.14 (d, J=1.96 Hz, 1H), 8.02 (dd, J=2.20, 8.31 Hz, 1H), 7.88 (d, J=8.56 Hz, 1H), 7.84 (d, J=8.31 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=2.20, 8.80 Hz, 1H), 6.97-7.07 (m, 2H), 6.87 (dd, J=4.28, 9.17 Hz, 2H), 6.36 (s, 1H), 4.47 (q, J=7.09 Hz, 2H), 3.49 (s, 3H), 1.23 (t, J=7.09 Hz, 3H); MS m/e 574.2 [M+H]⁺.

Example 14a was purified by chiral HPLC (Daicel Chiralpak AD, 100% EtOH) to give two enantiomers. The first eluting enantiomer was Example 14b and the second eluting enantiomer was Example 14c.

Example 14b

¹H NMR (400 MHz, MeOH-d₄) δ 8.78 (d, J=2.02 Hz, 1H), 8.14 (d, J=2.02 Hz, 1H), 8.02 (dd, J=2.02, 8.08 Hz, 1H), 7.88 (d, J=8.59 Hz, 1H), 7.84 (d, J=8.59 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=2.02, 8.59 Hz, 1H), 6.99-7.06 (m, 2H), 6.87 (dd, J=4.29, 9.35 Hz, 2H), 6.36 (d, J=1.01 Hz, 1H), 4.47 (q, J=7.07 Hz, 2H), 3.48 (s, 3H), 1.23 (t, J=7.07 Hz, 3H); MS m/e 574.2 [M+H]⁺.

Example 14c

¹H NMR (400 MHz, MeOH-d₄) δ 8.78 (d, J=2.02 Hz, 1H), 8.14 (d, J=2.02 Hz, 1H), 8.02 (dd, J=1.77, 8.34 Hz, 1H), 7.88 (d, J=8.59 Hz, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.75 (s, 1H), 7.66 (dd, J=2.02, 8.59 Hz, 1H), 7.03 (t, J=8.59 Hz, 2H), 6.87 (dd, J=4.55, 9.09 Hz, 2H), 6.36 (d, J=1.01 Hz, 1H), 4.47 (q, J=7.07 Hz, 2H), 3.48 (s, 3H), 1.23 (t, J=7.07 Hz, 3H); MS m/e 574.2 [M+H]⁺.

Example 15a (4-Chloro-2-methoxy-3-phenoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared using methanol and one equivalent of sodium methoxide in place of ethanol and sodium ethoxide, respectively according to the procedure of Example 2a. The TFA salt obtained was suspended in EtOAc and washed twice with saturated aqueous NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=2.02 Hz, 1H), 7.88 (d, J=8.84 Hz, 1H), 7.69 (s, 1H), 7.60 (dd, J=2.15, 8.72 Hz, 1H), 7.44 (d, J=8.59 Hz, 2H), 7.29-7.35 (m, 4H), 7.11 (s, 1H), 7.05-7.10 (m, 1H), 6.91 (dd, J=0.88, 8.72 Hz, 2H), 6.16 (d, J=1.01 Hz, 1H), 3.95 (s, 3H), 3.34 (br. s., 3H); MS m/e 507.1 [M+H]⁺.

Example 15a was purified by chiral HPLC (Daicel Chiralpak AD, 100% EtOH) to give two enantiomers. The first eluting enantiomer was Example 15b and the second eluting enantiomer was Example 15c.

Example 15b

¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (br. s., 1H), 8.07 (d, J=1.96 Hz, 1H), 7.90 (d, J=8.80 Hz, 1H), 7.61 (dd, J=1.96, 8.80 Hz, 1H), 7.46 (d, J=8.80 Hz, 2H), 7.28-7.38 (m, 5H), 7.05-7.11 (m, 1H), 6.90 (dd, J=0.86, 8.68 Hz, 2H), 6.46 (br. s., 1H), 3.96 (s, 3H), 3.42 (s, 3H); MS m/e 507.0 [M+H]⁺.

Example 15c

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (br. s., 1H), 8.08 (d, J=1.71 Hz, 1H), 7.91 (d, J=8.80 Hz, 1H), 7.61 (dd, J=1.96, 8.80 Hz, 1H), 7.48 (d, J=8.56 Hz, 2H), 7.41 (s, 1H), 7.37 (d, J=8.80 Hz, 2H), 7.33 (dd, J=7.58, 8.56 Hz, 2H), 7.05-7.11 (m, 1H), 6.90 (d, J=7.82 Hz, 2H), 6.65 (br. s., 1H), 3.96 (s, 3H), 3.46 (s, 3H); MS m/e 506.9 [M+H]⁺.

Example 16 (4-Chloro-2-(dimethylamino)-3-phenoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared using 6-bromo-4-chloro-N,N-dimethyl-3-phenoxyquinolin-2-amine (Intermediate 5, step e) in place of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (Intermediate 5, step d) according to the procedure of Example 5a. ¹H NMR (400 MHz, MeOH-d₄) δ 7.91 (d, J=2.02 Hz, 1H), 7.74 (d, J=8.59 Hz, 1H), 7.67 (br. s., 1H), 7.57 (dd, J=2.02, 9.09 Hz, 1H), 7.32-7.39 (m, 4H), 7.28 (dd, J=7.58, 8.59 Hz, 2H), 7.00-7.07 (m, 1H), 6.74 (d, J=7.58 Hz, 2H), 6.28 (br. s., 1H), 3.46 (s, 3H), 3.10 (s, 6H); MS m/e 520.8 [M+H]⁺.

Example 17 (4-Chloro-2-(dimethylamino)-3-phenoxyquinolin-6-yl)(6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared using 6-bromo-4-chloro-N,N-dimethyl-3-phenoxyquinolin-2-amine (Intermediate 5, step e) and (6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 4, step d) according to the procedure of Example 3a. ¹H NMR (400 MHz, MeOH-d₄) δ 8.01 (d, J=2.02 Hz, 1H), 7.93 (d, J=2.02 Hz, 1H), 7.72-7.86 (m, 2H), 7.68 (dd, J=2.53, 8.59 Hz, 1H), 7.56 (dd, J=2.02, 9.09 Hz, 1H), 7.25-7.32 (m, J=7.07, 8.59 Hz, 2H), 7.01-7.07 (m, 1H), 6.81 (d, J=8.59 Hz, 1H), 6.72-6.78 (m, 2H), 6.37 (br. s., 1H), 3.91 (s, 3H), 3.51 (s, 3H), 3.11 (s, 6H); MS m/e 516.9 [M+H]⁺.

Example 18 (2-Chloro-4-methoxy-3-phenoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was isolated as a by-product from the reaction of Example 15a. ¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.15 (d, J=2.02 Hz, 1H), 7.97 (d, J=9.09 Hz, 1H), 7.68 (dd, J=2.02, 8.59 Hz, 1H), 7.60 (s, 1H), 7.47-7.53 (m, 2H), 7.34-7.42 (m, 4H), 7.12 (t, J=7.33 Hz, 1H), 6.99 (s, 1H), 6.93 (d, J=8.08 Hz, 2H), 4.10 (s, 3H), 3.54 (s, 3H); MS m/e 507.7 [M+H]⁺.

Example 19 4-Chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenoxyquinoline-2-carbonitrile.TFA

To an oven-dried sealed-tube was added (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (25 mg, 0.049 mmol, Example 1), Pd₂ dba₃ (1.8 mg, 0.002 mmol), 1,1′-bis(diphenylphosphino)ferrocene (2.2 mg, 0.004 mmol), zinc cyanide (7.0 mg, 0.059 mmol) and zinc nanopowder (0.77 mg, 0.012 mmol) and nitrogen gas was bubbled through it for 2 minutes. To this solid mixture was added N,N-dimethylacetamide (0.5 mL) and heated at 120° C. for 7.5 hours. The resulting dark suspension was diluted with EtOAc and washed with water. The organic phase was dried (MgSO₄), filtered and concentrated. The residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.30 (dd, J=3.28, 5.31 Hz, 2H), 7.89 (dd, J=1.77, 8.84 Hz, 1H), 7.82 (s, 1H), 7.51 (d, J=8.59 Hz, 2H), 7.43 (d, J=8.59 Hz, 2H), 7.40 (dd, J=7.58, 8.59 Hz, 2H), 7.14-7.21 (m, 1H), 7.07 (d, J=8.08 Hz, 2H), 7.05 (s, 1H), 3.55 (s, 3H); MS m/e 502.0 [M+H]⁺.

Example 20 6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenoxyquinoline-2,4-dicarbonitrile.TFA

The title compound was isolated as a second product from the reaction of Example 19. ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (br. s., 1H), 8.35 (d, J=9.09 Hz, 1H), 8.13 (s, 1H), 7.92 (dd, J=1.52, 9.09 Hz, 1H), 7.87 (br. s., 1H), 7.40-7.54 (m, 6H), 7.23-7.35 (m, 3H), 7.05 (br. s., 1H), 3.55 (s, 3H); MS m/e 494.0 [M+H]⁺.

Example 21 4-Chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-3-phenoxyquinoline-2-carbonitrile.TFA

The title compound was prepared using (2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (Example 13) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 19. ¹H NMR (400 MHz, MeOH-d₄) δ 8.82 (d, J=2.02 Hz, 1H), 8.40 (d, J=2.02 Hz, 1H), 8.23 (d, J=9.09 Hz, 1H), 8.06 (dd, J=2.02, 8.59 Hz, 1H), 7.94 (dd, J=2.02, 9.09 Hz, 1H), 7.85 (d, J=8.08 Hz, 1H), 7.77 (s, 1H), 7.33-7.40 (m, 2H), 7.10-7.19 (m, 1H), 6.95 (d, J=8.08 Hz, 2H), 6.43 (s, 1H), 3.48 (s, 3H); MS m/e 536.8 [M+H]⁺.

Example 22a 6-(Hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-3-phenoxyquinoline-2,4-dicarbonitrile

The TFA salt of the title compound was isolated as a product from the reaction of Example 21. This salt was suspended in EtOAc and washed twice with saturated aqueous NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 8.81 (d, J=2.02 Hz, 1H), 8.28 (dd, J=3.54, 5.56 Hz, 2H), 8.07 (dd, J=2.02, 8.08 Hz, 1H), 7.96 (dd, J=2.02, 9.09 Hz, 1H), 7.85 (d, J=8.59 Hz, 1H), 7.78 (s, 1H), 7.44 (dd, J=7.58, 8.59 Hz, 2H), 7.23-7.28 (m, 1H), 7.12-7.17 (m, 2H), 6.45 (s, 1H), 3.48 (s, 3H); MS m/e 527.0 [M+H]⁺.

Example 22a was purified by chiral HPLC (Daicel Chiralcel OJ, 100% MeOH) to give two enantiomers. The first eluting enantiomer was Example 22b and the second eluting enantiomer was Example 22c.

Example 22b

¹H NMR (400 MHz, MeOH-d₄) δ 8.81 (d, J=1.52 Hz, 1H), 8.25-8.31 (m, 2H), 8.07 (dd, J=2.02, 8.59 Hz, 1H), 7.96 (dd, J=1.52, 9.09 Hz, 1H), 7.85 (d, J=8.59 Hz, 1H), 7.79 (br. s., 1H), 7.41-7.48 (m, 2H), 7.23-7.29 (m, 1H), 7.11-7.18 (m, 2H), 6.45 (br. s., 1H), 3.48 (s, 3H); MS m/e 527.0 [M+H]⁺.

Example 22c

¹H NMR (400 MHz, MeOH-d₄) δ 8.81 (d, J=1.52 Hz, 1H), 8.23-8.33 (m, 2H), 8.07 (dd, J=1.77, 8.34 Hz, 1H), 7.96 (dd, J=1.52, 9.09 Hz, 1H), 7.85 (d, J=8.08 Hz, 1H), 7.79 (br. s., 1H), 7.40-7.49 (m, 2H), 7.23-7.30 (m, 1H), 7.11-7.17 (m, 2H), 6.47 (br. s., 1H), 3.48 (s, 3H); MS m/e 527.0 [M+H]⁺.

Example 23 4-Chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-(4-fluorophenoxy)quinoline-2-carbonitrile.TFA

The title compound was prepared using (4-chlorophenyl)(2,4-dichloro-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 12) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 19. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (br. s., 1H), 8.29 (dd, J=3.54, 5.56 Hz, 2H), 7.89 (dd, J=1.77, 8.84 Hz, 1H), 7.78 (s, 1H), 7.51 (d, J=8.59 Hz, 2H), 7.43 (d, J=8.59 Hz, 2H), 7.20-7.27 (m, 2H), 7.12-7.18 (m, 2H), 7.00 (br. s., 1H), 3.53 (s, 3H); MS m/e 519.9 [M+H]⁺.

Example 24 3-(4-Chlorophenoxy)-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(trifluoromethyl)quinoline-2-carbonitrile

The title compound was prepared using (2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-6-yl(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (Example 46) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) and 2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl in place of 1,1′-bis(diphenylphosphino)ferrocene according to the procedure of Example 19. ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (br. s., 1H), 8.82 (d, J=2.02 Hz, 1H), 8.39 (d, J=9.09 Hz, 1H), 8.27 (s, 1H), 8.06-8.14 (m, 2H), 7.97-8.05 (m, 2H), 7.46 (d, J=9.09 Hz, 2H), 7.15 (d, J=9.09 Hz, 2H), 7.06 (br. s., 1H), 3.52 (s, 3H); MS m/e 605.1 [M+H]⁺.

Example 25a (3-(4-Chlorophenoxy)-2-ethoxy-4-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using 6-bromo-3-(4-chlorophenoxy)-2-ethoxy-4-(trifluoromethyl)quinoline (Intermediate 7, step f) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of Example 1 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated aqueous NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 8.76 (d, J=1.52 Hz, 1H), 8.06-8.10 (m, 1H), 8.01 (dd, J=2.02, 8.08 Hz, 1H), 7.93 (d, J=9.09 Hz, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.76 (br. s., 1H), 7.73 (dd, J=1.77, 8.84 Hz, 1H), 7.30 (d, J=8.59 Hz, 2H), 6.85 (d, J=8.59 Hz, 2H), 6.36 (br. s., 1H), 4.44 (q, J=7.07 Hz, 2H), 3.49 (s, 3H), 1.17 (t, J=7.07 Hz, 3H); MS m/e 624.2 [M+H]⁺.

Example 25a was purified by chiral HPLC (Daicel Chiralpak AD, 15% EtOH-Heptane) to give two enantiomers. The first eluting enantiomer was Example 25b and the second eluting enantiomer was Example 25c.

Example 25b

¹H NMR (400 MHz, MeOH-d₄) δ 8.76 (d, J=1.52 Hz, 1H), 8.05-8.11 (m, 1H), 8.01 (dd, J=1.77, 8.34 Hz, 1H), 7.93 (d, J=8.59 Hz, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.76 (br. s., 1H), 7.73 (dd, J=1.77, 8.84 Hz, 1H), 7.30 (d, J=9.09 Hz, 2H), 6.85 (d, J=9.09 Hz, 2H), 6.37 (br. s., 1H), 4.44 (q, J=7.07 Hz, 2H), 3.49 (s, 3H), 1.17 (t, J=7.07 Hz, 3H); MS m/e 624.2 [M+H]⁺.

Example 25c

¹H NMR (400 MHz, MeOH-d₄) δ 8.76 (d, J=2.02 Hz, 1H), 8.07 (br. s., 1H), 8.01 (dd, J=1.52, 8.08 Hz, 1H), 7.93 (d, J=9.09 Hz, 1H), 7.84 (d, J=8.08 Hz, 1H), 7.77 (br. s., 1H), 7.73 (dd, J=1.77, 8.84 Hz, 1H), 7.30 (d, J=8.59 Hz, 2H), 6.85 (d, J=8.59 Hz, 2H), 6.37 (br. s., 1H), 4.44 (q, J=7.07 Hz, 2H), 3.49 (s, 3H), 1.17 (t, J=7.07 Hz, 3H); MS m/e 624.2 [M+H]⁺.

Example 26 (3-(4-Chlorophenoxy)-2-(diethylamino)-4-(trifluoromethyl)quinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

The title compound was prepared using 6-bromo-3-(4-chlorophenoxy)-N,N-diethyl-4-(trifluoromethyl)quinolin-2-amine (Intermediate 7, step e) in place of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (Intermediate 5, step d) according to the procedure of Example 3a except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.98 (br. s., 1H), 7.94 (br. s., 1H), 7.86 (d, J=8.59 Hz, 1H), 7.65 (d, J=9.09 Hz, 1H), 7.45 (d, J=8.59 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.27 (d, J=9.09 Hz, 2H), 6.91 (br. s., 1H), 6.67 (d, J=8.59 Hz, 2H), 3.70 (s, 3H), 3.55 (q, J=6.91 Hz, 4H), 1.04 (t, J=7.07 Hz, 6H); MS m/e 616.8 [M+H]⁺.

Example 27a (3-(4-Chlorophenoxy)-2-(diethylamino)-4-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using 6-bromo-3-(4-chlorophenoxy)-N,N-diethyl-4-(trifluoromethyl)quinolin-2-amine (Intermediate 7, step e) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of Example 3a except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated aqueous NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 8.75 (d, J=2.02 Hz, 1H), 7.99 (dd, J=2.02, 8.59 Hz, 1H), 7.93-7.95 (m, 1H), 7.85 (d, J=6.57 Hz, 1H), 7.83 (d, J=5.56 Hz, 1H), 7.74 (br. s., 1H), 7.66 (dd, J=1.77, 8.84 Hz, 1H), 7.27 (d, J=8.59 Hz, 2H), 6.69 (d, J=9.09 Hz, 2H), 6.35 (br. s., 1H), 3.54 (q, J=6.74 Hz, 4H), 3.49 (s, 3H), 1.04 (t, J=6.82 Hz, 6H); MS m/e 651.1 [M+H]⁺.

Example 27a was purified by chiral HPLC (Daicel Chiralpak AD, 15% EtOH-Heptane) to give two enantiomers. The first eluting enantiomer was Example 27b and the second eluting enantiomer was Example 27c.

Example 27b

¹H NMR (400 MHz, MeOH-d₄) δ 8.75 (d, J=2.02 Hz, 1H), 7.99 (dd, J=2.02, 8.59 Hz, 1H), 7.94 (t, J=2.02 Hz, 1H), 7.81-7.87 (m, 2H), 7.74 (s, 1H), 7.66 (dd, J=2.02, 9.09 Hz, 1H), 7.27 (d, J=9.09 Hz, 2H), 6.68 (d, J=9.09 Hz, 2H), 6.35 (d, J=1.01 Hz, 1H), 3.54 (q, J=6.91 Hz, 4H), 3.49 (s, 3H), 1.04 (t, J=7.07 Hz, 6H); MS m/e 651.1 [M+H]⁺.

Example 27c

¹H NMR (400 MHz, MeOH-d₄) δ 8.75 (d, J=2.02 Hz, 1H), 7.99 (dd, J=2.27, 8.34 Hz, 1H), 7.92-7.95 (m, 1H), 7.81-7.88 (m, 2H), 7.74 (s, 1H), 7.66 (dd, J=2.02, 9.09 Hz, 1H), 7.27 (d, J=9.09 Hz, 2H), 6.68 (d, J=9.09 Hz, 2H), 6.35 (d, J=1.01 Hz, 1H), 3.54 (q, J=6.91 Hz, 4H), 3.49 (s, 3H), 1.04 (t, J=7.07 Hz, 6H); MS m/e 651.1 [M+H]⁺.

Example 28 (3-(4-Chlorophenoxy)-2-(diethylamino)-4-(trifluoromethyl)quinolin-6-yl)(6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

The title compound was prepared using 6-bromo-3-(4-chlorophenoxy)-N,N-diethyl-4-(trifluoromethyl)quinolin-2-amine (Intermediate 7, step e) and (6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 4, step d) according to the procedure of Example 3a except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 8.99 (s, 1H), 8.06 (d, J=2.53 Hz, 1H), 7.95-8.00 (m, 1H), 7.89 (d, J=8.59 Hz, 1H), 7.72 (dd, J=2.53, 8.59 Hz, 1H), 7.64 (dd, J=2.02, 9.09 Hz, 1H), 7.28 (d, J=9.09 Hz, 2H), 6.98 (d, J=1.52 Hz, 1H), 6.88 (d, J=8.59 Hz, 1H), 6.69 (d, J=9.09 Hz, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.56 (q, J=6.91 Hz, 4H), 1.05 (t, J=7.07 Hz, 6H); MS m/e 612.9 [M+H]⁺.

Example 29 (4-Chlorophenyl)(2-(diethylamino)-3-phenoxy-4-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

The title compound was prepared using 6-bromo-N,N-diethyl-3-phenoxy-4-(trifluoromethyl)quinolin-2-amine (Intermediate 8, step c) in place 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (Intermediate 5, step d) according to the procedure of Example 3a except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. ¹H NMR (400 MHz, MeOH-d₄) δ 8.97 (s, 1H), 7.90-7.93 (m, 1H), 7.85 (d, J=9.09 Hz, 1H), 7.64 (dd, J=2.02, 8.59 Hz, 1H), 7.45 (d, J=8.59 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.23-7.31 (m, 2H), 7.05 (t, J=6.82 Hz, 1H), 6.91 (s, 1H), 6.58-6.71 (m, 2H), 3.71 (s, 3H), 3.56 (q, J=7.07 Hz, 4H), 1.04 (t, J=7.07 Hz, 6H); MS m/e 581.8 [M+H]⁺.

Example 30a (2-(Azetidin-1-yl)-4-chloro-3-(4-chlorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using 2-(azetidin-1-yl)-6-bromo-4-chloro-3-(4-chlorophenoxy)quinoline (Intermediate 9, step d) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of

Example 3a

¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 7.85-7.97 (m, 3H), 7.73 (s, 1H), 7.69 (d, J=8.59 Hz, 1H), 7.47 (dd, J=2.02, 8.59 Hz, 1H), 7.34-7.42 (m, 3H), 6.91 (d, J=9.09 Hz, 2H), 6.22 (s, 1H), 4.11 (t, J=7.58 Hz, 4H), 3.34 (br. s., 3H), 2.14-2.29 (m, 2H); MS m/e 601.2 [M+H]⁺.

Example 30a was purified by chiral HPLC (Daicel Chiralpak AD-H, 2-Propanol, 20% i-propylamine) to give two enantiomers. The first eluting enantiomer was Example 30b and the second eluting enantiomer was Example 30c.

Example 30b

¹H NMR (400 MHz, MeOH-d₄) δ 8.75 (d, J=1.52 Hz, 1H), 8.00 (dd, J=2.02, 8.08 Hz, 1H), 7.95 (d, J=2.02 Hz, 1H), 7.82 (d, J=8.59 Hz, 1H), 7.70-7.79 (m, 2H), 7.55 (dd, J=2.02, 9.09 Hz, 1H), 7.31 (d, J=9.09 Hz, 2H), 6.81 (d, J=9.09 Hz, 2H), 6.35 (br. s., 1H), 4.23 (t, J=7.58 Hz, 4H), 3.48 (s, 3H), 2.31 (quin, J=7.45 Hz, 2H); MS m/e 601.2 [M+H]⁺.

Example 30c

¹H NMR (400 MHz, MeOH-d₄) δ 8.75 (d, J=2.02 Hz, 1H), 8.00 (dd, J=1.77, 8.34 Hz, 1H), 7.95 (d, J=2.02 Hz, 1H), 7.83 (d, J=8.08 Hz, 1H), 7.70-7.78 (m, 2H), 7.55 (dd, J=2.02, 8.59 Hz, 1H), 7.32 (d, J=9.09 Hz, 2H), 6.82 (d, J=9.09 Hz, 2H), 6.34 (br. s., 1H), 4.23 (t, J=7.58 Hz, 4H), 3.48 (s, 3H), 2.31 (quin, J=7.71 Hz, 2H); MS m/e 601.2 [M+H]⁺.

Example 31a 4-((2-(Azetidin-1-yl)-4-chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-3-yl)oxy)benzonitrile

The title compound was prepared using 4-((2-(azetidin-1-yl)-6-bromo-4-chloroquinolin-3-yl)oxy)benzonitrile (Intermediate 10, step e) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of Example 3a except the material from flash column chromatography was further purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated aqueous NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (d, J=1.01 Hz, 1H), 7.89-7.99 (m, 3H), 7.83 (d, J=9.09 Hz, 2H), 7.73 (s, 1H), 7.70 (d, J=9.09 Hz, 1H), 7.49 (dd, J=2.27, 8.84 Hz, 1H), 7.36 (s, 1H), 7.09 (d, J=9.09 Hz, 2H), 6.22 (d, J=1.01 Hz, 1H), 4.10 (t, J=7.58 Hz, 4H), 3.34 (s, 3H), 2.23 (quin, J=7.58 Hz, 2H); MS m/e 592.2 [M+H]⁺.

Example 31a was purified by chiral HPLC (Daicel Chiralpak AD, 2% i-propylamine in 20% Propanol-Heptane) to give two enantiomers. The first eluting enantiomer was Example 31b and the second eluting enantiomer was Example 31c.

Example 31b

¹H NMR (400 MHz, MeOH-d₄) δ 8.75 (d, J=2.02 Hz, 1H), 8.01 (dd, J=1.77, 8.34 Hz, 1H), 7.96 (d, J=2.02 Hz, 1H), 7.83 (d, J=8.08 Hz, 1H), 7.69-7.78 (m, 4H), 7.58 (dd, J=2.27, 8.84 Hz, 1H), 7.01 (d, J=9.09 Hz, 2H), 6.35 (br. s., 1H), 4.22 (t, J=7.58 Hz, 4H), 3.48 (s, 3H), 2.31 (quin, J=7.71 Hz, 2H); MS m/e 592.2 [M+H]⁺.

Example 31c

¹H NMR (400 MHz, MeOH-d₄) δ 8.75 (d, J=2.02 Hz, 1H), 8.01 (dd, J=2.27, 8.34 Hz, 1H), 7.96 (d, J=2.02 Hz, 1H), 7.83 (d, J=8.08 Hz, 1H), 7.69-7.78 (m, 4H), 7.58 (dd, J=2.27, 8.84 Hz, 1H), 7.01 (d, J=9.09 Hz, 2H), 6.34 (br. s., 1H), 4.22 (t, J=7.58 Hz, 4H), 3.48 (s, 3H), 2.31 (quin, J=7.58 Hz, 2H); MS m/e 592.2 [M+H]⁺.

Example 32a 4-((2-(Azetidin-1-yl)-4-chloro-6-((4-chlorophenyl)(hydroxyl)(1-methyl-1H-imidazol-5-yl)methyl)quinolin-3-yl)oxy)benzonitrile

The title compound was prepared using 4-((2-(azetidin-1-yl)-6-bromo-4-chloroquinolin-3-yl)oxy)benzonitrile (Intermediate 10, step e) according to the procedure of Example 3a except the material from flash column chromatography was further purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated aqueous NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 7.90 (d, J=2.02 Hz, 1H), 7.70-7.75 (m, 3H), 7.66 (s, 1H), 7.58 (dd, J=2.27, 8.84 Hz, 1H), 7.27-7.39 (m, 4H), 7.00 (d, J=8.59 Hz, 2H), 6.26 (s, 1H), 4.21 (t, J=7.58 Hz, 4H), 3.46 (s, 3H), 2.31 (quin, J=7.58 Hz, 2H); MS m/e 557.1 [M+H]⁺.

Example 32a was purified by chiral HPLC (Daicel Chiralcel OD, 0.2% i-propylamine in 100% Acetonitrile) to give two enantiomers. The first eluting enantiomer was Example 32b and the second eluting enantiomer was Example 32c.

Example 32b

¹H NMR (400 MHz, MeOH-d₄) δ 9.02 (s, 1H), 8.15 (d, J=2.02 Hz, 1H), 7.98 (d, J=8.59 Hz, 1H), 7.79-7.86 (m, 3H), 7.45 (d, J=8.59 Hz, 2H), 7.40 (d, J=8.59 Hz, 2H), 7.27 (d, J=8.59 Hz, 2H), 6.99 (s, 1H), 4.63 (t, J=7.83 Hz, 4H), 3.69 (s, 3H), 2.54 (quin, J=7.71 Hz, 2H); MS m/e 557.3 [M+H]⁺.

Example 32c

¹H NMR (400 MHz, MeOH-d₄) δ 9.02 (s, 1H), 8.16 (d, J=1.01 Hz, 1H), 7.99 (d, J=9.09 Hz, 1H), 7.78-7.86 (m, 3H), 7.45 (d, J=8.59 Hz, 2H), 7.40 (d, J=8.59 Hz, 2H), 7.28 (d, J=8.08 Hz, 2H), 6.99 (s, 1H), 4.63 (t, J=7.58 Hz, 4H), 3.69 (s, 3H), 2.54 (quin, J=7.71 Hz, 2H); MS m/e 557.2 [M+H]⁺.

Example 33 4-((4-Chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl) pyridin-3-yl)methyl)-2-(pyrrolidin-1-yl)quinolin-3-yl)oxy)benzonitrile

The title compound was prepared using 4-((6-bromo-4-chloro-2-(pyrrolidin-1-yl)quinolin-3-yl)oxy)benzonitrile (Intermediate 10, step f) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of Example 3a except the material from flash column chromatography was further purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated aqueous NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 9.01 (s, 1H), 8.79 (d, J=2.02 Hz, 1H), 8.07 (d, J=8.08 Hz, 1H), 7.96-8.03 (m, 1H), 7.88 (d, J=8.08 Hz, 1H), 7.77-7.86 (m, 1H), 7.73 (d, J=8.59 Hz, 2H), 7.53-7.63 (m, 1H), 7.07 (br. s., 1H), 6.97-7.04 (m, 2H), 3.71 (br. s., 7H), 1.92 (br. s., 4H); MS m/e 606.2 [M+H]⁺.

Example 34 (4-Chloro-2-((2-methoxyethyl)(methyl)amino)-3-phenxoyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol.TFA

The title compound was prepared using (2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (Example 13) and 2-methoxy-N-methylethanamine (5 equivalents) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) and diethylamine, respectively, according to the procedure described in Intermediate 5, step d. The material from flash column chromatography was further purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. ¹H NMR (400 MHz, MeOH-d₄) δ 9.03 (d, J=1.01 Hz, 1H), 8.81 (d, J=2.02 Hz, 1H), 8.07 (dd, J=2.27, 8.34 Hz, 1H), 8.05 (d, J=2.53 Hz, 1H), 7.87 (dd, J=8.59, 12.63 Hz, 2H), 7.61 (dd, J=2.02, 9.09 Hz, 1H), 7.27-7.34 (m, 2H), 7.04-7.12 (m, 2H), 6.80 (d, J=8.08 Hz, 2H), 3.85 (t, J=5.56 Hz, 2H), 3.72 (s, 3H), 3.57 (t, 2H), 3.24 (s, 3H), 3.24 (s, 3H); MS m/e 599.2 [M+H]⁺.

Example 35 (3-Chlorophenyl)(2,4-dichloro-3-(methyl(phenyl)amino)quinolin-6-yl)(pyridin-3-yl)methanol

To a solution of 6-bromo-2,4-dichloro-N-methyl-N-phenylquinolin-3-amine (85 mg, 0.22 mmol, Intermediate 11, step i) and (3-chlorophenyl)(pyridin-3-yl)methanone (53 mg, 0.25 mmol) in tetrahydrofuran (1 mL) at −78° C. was added n-butyllithium (1.6 M solution in hexanes, 0.181 mL, 0.289 mmol) dropwise and stirred at this temperature for 10 minutes and at room temperature for 12 hours. The resulting solution was cooled back to −78° C. and treated with (3-chlorophenyl)(pyridin-3-yl)methanone (53 mg, 0.25 mmol) and n-butyllithium (1.6 M solution in hexanes, 0.181 mL, 0.289 mmol) dropwise and stirred at this temperature for 10 minutes and at room temperature for 12 hours. The resulting solution was quenched with water and diluted with EtOAc. The organic phase was dried (MgSO₄), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 30% EtOAc-Heptane), affording the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=4.55 Hz, 1H), 8.49 (br. s., 1H), 8.13 (dd, J=2.02, 4.55 Hz, 1H), 8.06 (d, J=8.59 Hz, 1H), 7.74-7.86 (m, 1H), 7.61-7.74 (m, 1H), 7.35-7.52 (m, 4H), 7.28 (s, 1H), 7.11-7.25 (m, 3H), 6.75 (t, J=7.33 Hz, 1H), 6.52 (d, J=8.08 Hz, 2H), 3.26 (s, 3H); MS m/e 521.8 [M+H]⁺.

Example 36 (4-Chloro-2-ethoxy-3-(methyl(phenyl)amino)quinolin-6-yl)(3-chlorophenyl) (pyridin-3-yl)methanol.TFA

A mixture of (3-chlorophenyl)(2,4-dichloro-3-(methyl(phenyl)amino)quinolin-6-yl)(pyridin-3-yl)methanol (15 mg, 0.029 mmol, Example 35) and sodium ethoxide (0.5 mL, 21 wt. % solution in ethanol) was heated at 100° C. for 2 hours. The resulting reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried (MgSO₄), filtered and concentrated. The residue was purified via reverse phase HPLC with water/acetonitrile/0.1% TFA to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=7.82 Hz, 1H), 7.84 (d, J=8.80 Hz, 1H), 7.60 (d, J=8.56 Hz, 2H), 7.36-7.50 (m, 3H), 7.25-7.34 (m, 1H), 7.18-7.25 (m, 1H), 7.15 (t, J=7.70 Hz, 2H), 6.72 (t, J=7.21 Hz, 1H), 6.50 (d, J=8.07 Hz, 2H), 4.35-4.49 (m, 2H), 3.19 (s, 3H), 1.17 (t, J=6.97 Hz, 3H); MS m/e 531.9 [M+H]⁺.

Example 37 (3-Chlorophenyl)(2,4-diethoxy-3-(methyl(phenyl)amino)quinolin-6-yl)(pyridin-3-yl)methanol

The title compound was isolated as an additional product from the reaction of Example 36. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (d, J=4.04 Hz, 1H), 8.58 (s, 1H), 7.90 (d, J=8.08 Hz, 1H), 7.77 (d, J=2.53 Hz, 1H), 7.73 (d, J=8.59 Hz, 1H), 7.60 (dd, J=5.31, 7.83 Hz, 1H), 7.54 (dd, J=2.27, 8.84 Hz, 1H), 7.40-7.44 (m, 2H), 7.39 (s, 1H), 7.21 (td, J=2.02, 4.29 Hz, 1H), 7.14 (dd, J=7.07, 8.59 Hz, 3H), 6.68 (t, J=7.33 Hz, 1H), 6.50 (d, J=8.08 Hz, 2H), 4.36 (q, J=7.07 Hz, 2H), 4.04 (q, J=6.91 Hz, 2H), 3.16 (s, 3H), 1.16 (t, J=7.07 Hz, 3H), 1.08 (t, J=7.07 Hz, 3H); MS m/e 540.9 [M+H]⁺.

Example 38 (4-Chlorophenyl)(2,4-dichloro-3-(methyl(phenyl)amino)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared using (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) in place of (3-chlorophenyl)(pyridin-3-yl)methanone according to the procedure of Example 35. ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.23 (dd, J=1.52, 13.64 Hz, 1H), 8.11 (dd, J=1.77, 8.84 Hz, 1H), 7.77-7.84 (m, 1H), 7.74 (br. s., 1H), 7.46-7.55 (m, 2H), 7.42 (dd, J=3.03, 8.59 Hz, 2H), 7.19 (td, J=3.03, 7.83 Hz, 2H), 7.04 (s, 1H), 6.77 (t, J=7.07 Hz, 1H), 6.52 (d, J=8.08 Hz, 2H), 3.55 (s, 3H), 3.27 (s, 3H); MS m/e 524.8 [M+H]⁺.

Example 39 (3-Chlorophenyl)(2,4-dichloro-3-(ethyl(phenyl)amino)quinolin-6-yl)(pyridin-3-yl)methanol

The title compound was prepared using 6-bromo-2,4-dichloro-N-ethyl-N-phenylquinolin-3-amine (Intermediate 11, step j) in place of 6-bromo-2,4-dichloro-N-methyl-N-phenylquinolin-3-amine (Intermediate 11, step i) according to the procedure of Example 35. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=4.04 Hz, 1H), 8.49 (t, J=2.27 Hz, 1H), 8.15 (t, J=2.27 Hz, 1H), 8.06 (d, J=9.09 Hz, 1H), 7.79 (dt, J=2.34, 8.97 Hz, 1H), 7.68 (dd, J=1.26, 8.34 Hz, 1H), 7.36-7.48 (m, 4H), 7.27 (s, 1H), 7.19-7.25 (m, 1H), 7.13-7.19 (m, 2H), 6.74 (t, J=7.33 Hz, 1H), 6.52 (d, J=8.08 Hz, 2H), 3.62-3.84 (m, 2H), 0.83-0.88 (m, 3H); MS m/e 535.8 [M+H]⁺.

Example 40 (4-Chlorophenyl)(2,4-dichloro-3-(ethyl(phenyl)amino)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

The title compound was prepared using 6-bromo-2,4-dichloro-N-ethyl-N-phenylquinolin-3-amine (Intermediate 11, step j) and (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 35 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.24 (d, J=10.61 Hz, 1H), 8.11 (d, J=8.59 Hz, 1H), 7.76-7.85 (m, 1H), 7.73 (br. s., 1H), 7.47-7.55 (m, 2H), 7.38-7.47 (m, 2H), 7.12-7.22 (m, 2H), 7.04 (s, 1H), 6.75 (t, J=7.33 Hz, 1H), 6.52 (d, J=8.08 Hz, 2H), 3.67 (m, 2H), 3.55 (s, 3H), 1.21 (t, J=7.07 Hz, 3H); MS m/e 538.8 [M+H]⁺.

Example 41 (4-Chlorophenyl)(2,4-dichloro-3-(isopropyl(phenyl)amino)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

The title compound was prepared using 6-bromo-2,4-dichloro-N-isopropyl-N-phenylquinolin-3-amine (Intermediate 11, step k) and (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 35 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.25 (dd, J=1.96, 12.23 Hz, 1H), 8.10 (dd, J=2.45, 9.05 Hz, 1H), 7.81 (ddd, J=2.08, 8.93, 14.18 Hz, 1H), 7.73 (br. s., 1H), 7.51 (d, J=8.56 Hz, 2H), 7.43 (d, J=8.80 Hz, 2H), 7.17 (ddd, J=3.55, 7.34, 8.68 Hz, 2H), 7.06 (dd, J=1.22, 5.62 Hz, 1H), 6.70-6.79 (m, 1H), 6.52 (d, J=8.31 Hz, 2H), 4.34 (dt, J=6.30, 12.84 Hz, 1H), 3.56 (s, 3H), 1.31 (dd, J=1.22, 6.11 Hz, 3H), 1.15-1.19 (m, 3H); MS m/e 552.9 [M+H]⁺.

Example 42 (3-Chlorophenyl)(2,4-dichloro-3-(phenylamino)quinolin-6-yl)(pyridin-3-yl)methanol.TFA

The title compound was prepared using tert-butyl (6-bromo-2,4-dichloroquinolin-3-yl)(phenyl)carbamate (Intermediate 11, step e) in place of 6-bromo-2,4-dichloro-N-methyl-N-phenylquinolin-3-amine (Intermediate 11, step i) according to the procedure of Example 35 except the product from the reaction was treated with trifluoroacetic acid (2.5 mL, 10% solution in DCM) and stirred at room temperature for 14 hours and at 50° C. for 2 hours. The resulting mixture was concentrated and the residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (d, J=4.89 Hz, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.12 (d, J=1.71 Hz, 1H), 8.02 (d, J=8.80 Hz, 2H), 7.65-7.75 (m, 2H), 7.40-7.46 (m, 3H), 7.25 (dd, J=3.06, 6.48 Hz, 1H), 7.16 (t, J=7.82 Hz, 2H), 6.78 (t, J=7.21 Hz, 1H), 6.64 (d, J=7.82 Hz, 2H); MS m/e 506.8.

Example 43 (4-Chlorophenyl)(2,4-dichloro-3-(phenylamino)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

The title compound was prepared using tert-butyl (6-bromo-2,4-dichloroquinolin-3-yl)(phenyl)carbamate (Intermediate 11, step e) and (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 35 except the product from the reaction was dissolved in DCM (1 mL), treated with trifluoroacetic acid (0.5 mL) and stirred at 50° C. for 2 hours. The resulting mixture was concentrated and the residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03-9.14 (m, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.05 (d, J=8.84 Hz, 1H), 7.63-7.75 (m, 2H), 7.50 (d, J=8.34 Hz, 2H), 7.41 (d, J=8.34 Hz, 2H), 7.16 (t, J=7.83 Hz, 2H), 6.99 (br. s., 1H), 6.79 (t, J=7.33 Hz, 1H), 6.64 (d, J=8.08 Hz, 2H), 3.54 (s, 3H); MS m/e 510.8 [M+H]⁺.

Example 44 tert-Butyl (4-chloro-6-((4-chlorophenyl)(hydroxyl)(1-methyl-1H-imidazol-5-yl)methyl)-2-(diethylamino)quinolin-3-yl)(phenyl)carbamate.TFA

The title compound was prepared using tert-butyl (6-bromo-4-chloro-2-(diethylamino)quinolin-3-yl)(phenyl)carbamate (Intermediate 11, step 1) and (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 1, step b) according to the procedure of Example 35 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.06 (br. s., 1H), 7.73 (dd, J=1.71, 8.80 Hz, 1H), 7.46-7.60 (m, 4H), 7.37-7.46 (m, 2H), 7.22-7.32 (m, 2H), 7.09-7.19 (m, 3H), 6.99-7.09 (m, 1H), 3.65 (td, J=7.34, 13.82 Hz, 2H), 3.56 (s, 3H), 3.12-3.21 (m, 2H), 1.43 (s, 9H), 0.83-0.92 (m, 6H); MS m/e 647.0 [M+H]⁺.

Example 45 (4-Chloro-2-(diethylamino)-3-(phenylamino)quinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

To a solution of tert-butyl (4-chloro-6-((4-chlorophenyl)(hydroxyl)(1-methyl-1H-imidazol-5-yl)methyl)-2-(diethylamino)quinolin-3-yl)(phenyl)carbamate.TFA (25 mg, 0.039 mmol, Example 44) in DCM (1.2 mL) was added trifluoroacetic acid (0.5 mL) and stirred at 50° C. for 2 hours. The resulting mixture was concentrated and the residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA. ¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.71 (d, J=8.56 Hz, 1H), 7.41-7.55 (m, 4H), 7.38 (d, J=8.31 Hz, 2H), 7.12 (t, J=7.58 Hz, 2H), 7.01 (s, 1H), 6.71 (t, J=7.21 Hz, 1H), 6.56 (d, J=8.07 Hz, 2H), 3.56 (s, 3H), 3.42 (m, 4H), 1.02 (t, J=6.85 Hz, 6H); MS m/e 548.0 [M+H]⁺.

Example 46 (2-Chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared using 6-bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline (Intermediate 7, step d) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate 2, step c) according to the procedure of Example 1 except the crude residue was purified by reverse phase HPLC with water/acetonitrile/0.1% TFA to obtain the product as a trifluoroacetic acid salt. The salt was suspended in EtOAc and washed twice with saturated NaHCO₃ solution. The organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ 8.78 (d, J=1.96 Hz, 1H), 8.26 (t, J=1.83 Hz, 1H), 8.14 (d, J=9.05 Hz, 1H), 8.04 (dd, J=2.20, 8.31 Hz, 1H), 7.93 (dd, J=1.83, 8.93 Hz, 1H), 7.85 (d, J=8.31 Hz, 1H), 7.77 (s, 1H), 7.34 (d, J=9.05 Hz, 2H), 6.88 (d, J=9.05 Hz, 2H), 6.41 (s, 1H), 3.49 (s, 3H); MS m/e 614.0 [M+H]⁺.

In Vitro Biological Data

ThermoFluor® Assay

ThermoFluor® is a fluorescence based assay that estimates ligand binding affinities by measuring the effect of a ligand on protein thermal stability (Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R. (2001) High-density miniaturized thermal shift assays as a general strategy for drug discovery. J Biomol Screen 6, 429-40, and Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005) Thermodynamic stability of carbonic anhydrase: measurements of binding affinity and stoichiometry using ThermoFluor. Biochemistry 44, 5258-66). This approach is applicable to a wide variety of systems, and rigorous in theoretical interpretation through quantitation of equilibrium binding constants (K_(D)).

In a ThermoFluor® experiment where protein stability is monitored as the temperature is steadily increased, an equilibrium binding ligand causes the midpoint of an unfolding transition (T_(m)) to occur at a higher temperature. The shift in the melting point described as a ΔT_(m) is proportional to the concentration and affinity of the ligand. The compound potency may be compared as a rank order of either ΔT_(m) values at a single compound concentration or in terms of K_(D) values, estimated from concentration response curves.

RORγt ThermoFluor® Assay Construct

For the RORγt construct used in the ThermoFluor® assay, numbering for the nucleotide sequences was based on the reference sequence for human RORγt, transcript variant 2, NCBI Accession: NM_001001523.1 (SEQ ID NO:1). Nucleotides 850-1635 (SEQ ID NO:2) coding for the wild type human RORγt ligand binding domain (RORγt LBD) were cloned into the pHIS1 vector, a modified pET E. coli expression vector (Accelagen, San Diego), containing an in-frame N-terminal His-tag and a TurboTEV protease cleavage site (ENLYFQG, SEQ ID NO:3) upstream of the cloned insert sequence. The amino acid sequence for the RORγt construct used in the Thermofluor assay is shown as SEQ ID NO:4.

ThermoFluor® experiments were carried out using instruments owned by Janssen Research and Discovery, L.L.C. through its acquisition of 3-Dimensional Pharmaceuticals, Inc. 1,8-ANS (Invitrogen) was used as a fluorescent dye. Protein and compound solutions are dispensed into black 384-well polypropylene PCR microplates (Abgene) and overlayed with silicone oil (1 μL, Fluka, type DC 200) to prevent evaporation.

Bar-coded assay plates are robotically loaded onto a thermostatically controlled PCR-type thermal block and then heated at a typical ramp-rate of 1° C./min for all experiments. Fluorescence was measured by continuous illumination with UV light (Hamamatsu LC6) supplied via fiber optic and filtered through a band-pass filter (380-400 nm; >60D cutoff). Fluorescence emission of the entire 384-well plate was detected by measuring light intensity using a CCD camera (Sensys, Roper Scientific) filtered to detect 500±25 nm, resulting in simultaneous and independent readings of all 384 wells. Images were collected at each temperature, and the sum of the pixel intensity in a given area of the assay plate was recorded versus temperature. Reference wells contained RORγt without compounds, and the assay conditions were as follows:

-   -   0.065 mg/mL RORγt     -   60 μM 1,8-ANS     -   100 mM Hepes, pH 7.0     -   10 mM NaCl     -   2.5 mM GSH     -   0.002% Tween-20

Project compounds were arranged in a pre-dosed mother plate (Greiner Bio-one) wherein compounds are serially diluted in 100% DMSO by 1:2 from a high concentration of 10 mM over 12 columns within a series (column 12 is a reference well containing DMSO, no compound). The compounds were robotically dispensed directly into assay plates (1x=46 mL) using a Hummingbird capillary liquid handling instrument (Digilab). Following compound dispense, protein and dye in buffer was added to achieve the final assay volume of 3 μL, followed by 1 μL of silicone oil.

The binding affinity was estimated as described previously (Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005) Thermodynamic stability of carbonic anhydrase: measurements of binding affinity and stoichiometry using ThermoFluor®. Biochemistry 44, 5258-66) using the following thermodynamic parameters of protein unfolding:

-   Reference RORγt T_(m): 47.8° C. -   ΔH_((Tm))=115 kcal/mol -   ΔC_(p (Tm))=3 kcal/mol     Cell Based Biological Data     RORγt Reporter Assay

A reporter assay was used to test functional activity of RORγt modulatory compounds on transcriptional activation driven by the RORγt LBD. Cells used in the assay were co-transfected with two constructs. The first construct, pBIND-RORγt LBD, contained the wild type human RORγt LBD fused to the DNA binding domain of the GAL4 protein. The second construct, pGL4.31 (Promega Cat no. C935A), contained multiple GAL4 responsive DNA elements upstream of firefly luciferase. To generate a background control, cells were similarly co-transfected with two constructs, but in the first construct the AF2 amino acid motif in the RORγt LBD was changed from LYKELF (SEQ ID NO:5) to LFKELF (SEQ ID NO:6). The AF2 mutation has been shown to prevent co-activator binding to the RORγt LBD, thus preventing transcription of firefly luciferase. The mutant construct was called pBIND-RORγt-AF2. For the RORγt constructs used in the reporter assay, numbering for the nucleotide sequences was also based on the reference sequence for human RORγt, transcript variant 2, NCBI Accession: NM_001001523.1 (SEQ ID NO:1). For the wild type human RORγt LBD construct, pBIND-RORγt LBD, nucleotides 850-1635 (SEQ ID NO:2) coding for the wild type human RORγt LBD were cloned into EcoRI and NotI sites in the pBIND vector (Promega cat. No E245A). The pBIND vector contains the GAL4 DNA Binding Domain (GAL4 DBD) and the renilla luciferase gene under control of the SV40 promoter. Renilla luciferase expression serves as a control for transfection efficiency and cell viability. For the background control construct, pBIND-RORγt-AF2, the AF2 domain of RORγt LBD was mutated using the Quik Change II Site Directed Mutagenesis System (Stratagene Cat. No. 200519). The nucleotide sequence coding for the RORγt LBD sequence with the mutated AF2 domain is shown as SEQ ID NO:7. The amino acid sequences for the wild type RORγt LBD and RORγt LBD with the mutated AF2 domain are shown as SEQ ID NO:8 and SEQ ID NO:9, respectively.

The reporter assay was performed by transiently transfecting HEK293T cells with 5 μg of pBIND-RORγt LBD or pBIND-RORγt LBD-AF2 and 5 μg pGL4.31 (Promega Cat no. C935A) using Fugene 6 (Invitrogen Cat no. E2691) at a 1:6 ratio of DNA: Fugene 6 in a T-75 flask in which cells were at least 80% confluent. Twenty four hours after bulk transfection, cells were plated into 96-well plates at 50,000 cells/well in phenol-red free DMEM containing 5% Lipid Reduced FCS and Pen/Strep. Six hours after plating, cells were treated with compounds for 24 hours. Media was removed and cells were lysed with 50 μL 1x Glo Lysis Buffer (Promega). Dual Glo Luciferase Reagent (50 μL/well) was then added and firefly luciferase luminescence was read on an Envision after a ten minute incubation. Finally, Stop and Glo reagent (50 μL/well) was added and renilla luciferase luminescence was read on an Envision after a ten minute incubation. To calculate the effect of compounds on RORγt activity, the ratio of firefly to renilla luciferase was determined and plotted against compound concentration. Agonist compounds increase RORγt-driven luciferase expression, and antagonist or inverse agonist compounds decrease luciferase expression.

Human Th17 Assay

The human Th17 assay tests the effect of RORγt modulatory compounds on IL-17 production by CD4 T cells under conditions which favor Th17 differentiation.

Total CD4⁺ T cells were isolated from the peripheral blood mononuclear cells (PBMC) of healthy donors using a CD4⁺ T cell isolation kit II, following the manufacturer's instructions (Miltenyi Biotec). Cells were resuspended in a medium of RPMI-1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin, glutamate, and β-mercaptoethanol and were added to 96-well plates at 1.5×10⁵ per 100 μL per well. 50 μL of compound at titrated concentrations in DMSO were added into each well at final DMSO concentration at 0.2%. Cells were incubated for 1 hour, then 50 μL of Th17 cell differentiation medium was added to each well. The final concentrations of antibodies and cytokines (R&D Systems) in differentiation medium were: 3×10⁶/mL anti-CD3/CD28 beads (prepared using human T cell activation/expansion kit, Miltenyi Biotec), 10 μg/mL anti-IL4, 10 μg/mL anti-IFNγ, 10 ng/mL IL113, 10 ng/mL IL23, 50 ng/mL IL6, 3 ng/mL TGFβ and 20 U/mL IL2. Cells were cultured at 37° C. and 5% CO₂ for 3 days. Supernatants were collected and the accumulated IL-17 in culture was measured by using MULTI-SPOT® Cytokine Plate following manufacture's instruction (Meso Scale Discovery). The plate was read using Sector Imager 6000, and IL-17 concentration was extrapolated from the standard curve. The IC50s were determined by GraphPad.

TABLE 1 RORγt reporter RORγt Assay, % Human Th17 ThermoFluor ® reporter inhibition @ Assay, Example Assay, Kd μM Assay, IC₅₀ μM 6 μM IC₅₀ μM 1 0.11 0.67 86 ND 2a 0.084 0.41 88 0.61 2b 0.48 0.37 92 0.66 2c 0.041 0.26, ~0.4 92 0.21 3a 0.059 0.12 96 0.2 3b 0.32 1.4 77 ND 3c 0.017 0.16 104 0.12 4 0.014 0.67, ~0.5 92 ND 5a 0.012 ~0.1 104 0.13 5b 0.012 0.039 98 0.085 5c 0.026 0.028 104 0.11 6a 0.051 0.085 102 0.096 6b 0.0083 0.081 93 0.05 6c 0.17 0.27 88 0.21 7 0.034 0.072 91 0.11 8 0.0072 0.016 95 0.048 9a 0.033 ~0.3 97 ND 9b 0.081 0.22 81 0.32 9c 0.008 0.066 84 0.092 10a 0.0085 0.087 95 0.093, ~1 10b 0.0034 0.092 97 0.078 10c 0.039 0.27 103 0.095 11 ND ND ND ND 12 ND ND ND ND 13 ND ND ND ND 14a 0.022 ~6 55 ND 14b 0.034 1.1, ~0.7, ~2, 69 ND ~1 14c 0.01 >6 18 ND 15a 0.15 0.75 83 ND 15b 0.3 ~2 86 ND 15c 0.033 ~0.7 82 ND 16 0.031 0.36 94 0.1 17 0.0041 0.15 99 0.11 18 1.7 2.1 88 ND 19 0.032 0.41 85 0.17 20 0.0057 0.11 97 0.04 21 ND ~2, ~4 80 ND 22a ND ~6 55 ND 22b 0.0029 ~6, >6 48 ND 22c 0.097 0.68 88 ND 23 0.026 1.2, ~0.7, ~2 80 ND 24 0.0042 ~6, >6, ~5 55 ND 25a 0.061 0.56 75 ND 25b 0.08 0.25 92 0.44 25c 0.02 ~2, ~1 67 ND 26 0.1 0.36 89 0.51 27a 0.075 0.21 89 0.18 27b 0.014 0.01 92 0.051 27c 1.4 0.095 89 0.49 28 0.072 0.11 99 0.12 29 0.17 0.47 93 ND 30a 0.0018 0.14 93 ND 30b 0.0089 0.031 103 0.064 30c 0.00053 0.058 97 0.02 31a 0.0036 0.088 90 ND 31b 0.014 0.018 99 ~0.1 31c 0.00072 0.19 96 0.017 32a 0.0069 0.072 102 ND 32b 0.032 0.12 101 0.11 32c 0.0033 0.066 101 0.056 33 0.066 0.28 99 0.088 34 0.018 0.25 95 ND 35 0.023 ~0.1 92 ~1 36 0.032 0.089 89 0.16 37 5.7 ND ND ND 38 0.035 0.52, ~1 85 ND 39 0.82 0.17 58 >6 40 0.79 0.49 74 ND 41 0.43 ~1 91 ND 42 0.037 0.92 110 ND 43 0.11 0.88 97 ND 44 0.71 ~2 62 ND 45 0.27 0.81 91 ND 46 ND >6 39 ND All data shown in Table 1 is either the value of one data point or the average of more than one data point. In cases where more than one value is shown in a table cell, values with qualifiers such as ~, > or < shown on the right side of the table cell could not be included in the averaging calculation for the value shown on the left side of the table cell. ND—no data

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

All documents cited herein are incorporated by reference. 

What is claimed is:
 1. A compound of Formula I

wherein: R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, quinazolinyl, cinnolinyl, benzothiazolyl, indazolyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, benzimidazolyl, indolyl, thiadiazolyl, oxadiazolyl or quinolinyl; wherein said pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, quinazolinyl, cinnolinyl, benzothiazolyl, indazolyl, imidazolyl, phenyl, thiophenyl, benzoxazolyl, benzimidazolyl, indolyl, quinolinyl, and pyrazolyl are optionally substituted with C(O)C₍₁₋₄₎alkyl, C(O)NH₂, C(O)NHC₍₁₋₂₎alkyl, C(O)N(C₍₁₋₂₎alkyl)₂, NHC(O)C₍₁₋₄₎alkyl, NHSO₂C₍₁₋₄₎alkyl, C₍₁₋₄₎alkyl, CF₃, CH₂CF₃, Cl, F, —CN, OC₍₁₋₄₎alkyl, N(C₍₁₋₄₎alkyl)₂, —(CH₂)₃OCH₃, SC₍₁₋₄₎alkyl, OH, CO₂H, CO₂C₍₁₋₄₎alkyl, C(O)CF₃, SO₂CF₃, OCF₃, OCHF₂, SO₂CH₃, SO₂NH₂, SO₂NHC₍₁₋₂₎alkyl, SO₂N(C₍₁₋₂₎alkyl)₂, C(O)NHSO₂CH₃, or OCH₂OCH₃; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, and F; and wherein said triazolyl, oxazolyl, isoxazolyl, pyrrolyl, and thiazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl; and said thiadiazolyl and oxadiazolyl are optionally substituted with C₍₁₋₂₎alkyl; and said pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl are optionally substituted with up to three additional substituents independently selected from the group consisting of C(O)NHC₍₁₋₂₎alkyl, C(O)N(C₍₁₋₂₎alkyl)₂, NHC(O)C₍₁₋₄₎alkyl, NHSO₂C₍₁₋₄₎alkyl, C(O)CF₃, SO₂CF₃, SO₂NHC₍₁₋₂₎alkyl, SO₂N(C₍₁₋₂₎alkyl)₂, C(O)NHSO₂CH₃, SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₄₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SC₍₁₋₄₎alkyl, CF₃, F, Cl, and C₍₁₋₄₎alkyl; R² is triazolyl, pyridyl, pyridyl-N-oxide, pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N-C₍₁₋₃₎alkyl-piperidinyl, thiazolyl, pyridazyl, pyrazinyl, 1-(3-methoxypropyl)-imidazolyl, thiadiazolyl, oxadiazolyl, or imidazolyl; wherein said imidazolyl is optionally substituted with up to three additional substituents independently selected from the group consisting of C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, F, and Cl; and said pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazyl, and pyrazinyl, are optionally substituted with up to three additional substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, or C₍₁₋₂₎alkyl; and said triazolyl, thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl; and said thiadiazolyl and oxadiazolyl are optionally substituted with C₍₁₋₂₎alkyl; and said pyrazolyl is optionally substituted with up to three CH₃ groups; R³ is H, OH, OCH₃, or NH₂; R⁴ is H, or F; R⁵ is H, Cl, —CN, CF₃, SC₍₁₋₄₎alkyl, OC₍₁₋₄₎alkyl, OH, C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₄₎alkyl), N(C₍₁₋₄₎alkyl)₂, or 4-hydroxy-piperidinyl; R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl, —N(CO₂C(CH₃)₃)phenyl, N(COCH₃)phenyl, —O-pyridyl, —NHpyridyl, —N(C₍₁₋₃₎alkyl)pyridyl, N(CO₂C(CH₃)₃)pyridyl, N(COCH₃)pyridyl, —O-pyrimidinyl, —NHpyrimidinyl, —N(C₍₁₋₃₎alkyl)pyrimidinyl, N(CO₂C(CH₃)₃)pyrimidinyl, N(COCH₃)pyrimidinyl, —O-pyridazyl, —NHpyridazyl, —N(C₍₁₋₃₎alkyl)pyridazyl, N(CO₂C(CH₃)₃)pyridazyl, N(COCH₃)pyridazyl, —O-pyrazinyl, —NHpyrazinyl, —N(C₍₁₋₃₎alkyl)pyrazinyl, N(CO₂C(CH₃)₃)pyrazinyl, or N(COCH₃)pyrazinyl; wherein said pyrimidinyl, pyridazyl, or pyrazinyl are optionally substituted with Cl, F, CH₃, SCH₃, OC₍₁₋₄₎alkyl, —CN, CONH₂, SO₂NH₂, or SO₂CH₃; and wherein said phenyl or said pyridyl is optionally substituted up to two times with OCF₃, SO₂C₍₁₋₄₎alkyl, CF₃, CHF₂, pyrazolyl, triazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, C₍₁₋₄₎alkyl, C₍₃₋₄₎cycloalkyl, OC₍₁₋₄₎alkyl, N(CH₃)₂, SO₂NH₂, SO₂NHCH₃, SO₂N (CH₃)₂, CONH₂, CONHCH₃, CON(CH₃)₂, Cl, F, —CN, CO₂H, OH, CH₂OH, NHCOC₍₁₋₂₎alkyl, COC₍₁₋₂₎alkyl, SCH₃, CO₂C₍₁₋₄₎alkyl, NH₂, NHC₍₁₋₂₎alkyl, or OCH₂CF₃; wherein the selction of each optional substituent is independent; and wherein said pyrazolyl, triazolyl, imidazolyl, tetrazolyl, oxazolyl, and thiazolyl are optionally substituted with CH₃; R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₄₎alkylCF₃, OCF₃, OCHF₂, OCH₂CH₂OC₍₁₋₄₎alkyl, CF₃, SCH₃, C₍₁₋₄₎alkylNA¹A², CH₂OC₍₂₋₃₎alkylNA¹A², NA¹A², C(O)NA¹A², CH₂NHC₍₂₋₃₎alkylNA¹A², CH₂N(CH₃)C₍₂₋₃₎alkylNA¹A²,NHC₍₂₋₃₎alkylNA¹A², N(CH₃)C₍₂₋₄₎alkylNA¹A², OC₍₂₋₄₎alkylNA¹A², OC₍₁₋₄₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl, phenyl, thiophenyl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, or pyrimidinyl; wherein said phenyl, thiophenyl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, and pyrimidinyl are optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, CH₃, CF₃, and OCH₃; A¹ is H, or C₍₁₋₄₎alkyl; A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₄₎alkyl, or OC₍₁₋₄₎alkyl; or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

R_(a) is H, OC₍₁₋₄₎alkyl, CH₂OH, NH(CH₃), N(CH₃)₂, NH₂, CH₃, F, CF₃, SO₂CH₃, or OH; R_(b) is H, CO₂C(CH₃)₃, C₍₁₋₄₎alkyl, C(O)C₍₁₋₄₎alkyl, SO₂C₍₁₋₄₎alkyl, CH₂CH₂CF₃, CH₂CF₃, CH₂-cyclopropyl, phenyl, CH₂-phenyl, or C₍₃₋₆₎cycloalkyl; R⁸ is H, C₍₁₋₃₎alkyl, OC₍₁₋₃₎alkyl, CF₃, NH₂, NHCH₃, —CN, or F; R⁹ is H, or F; and pharmaceutically acceptable salts thereof.
 2. A compound of claim 1 wherein: R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl, imidazolyl, phenyl, thiophenyl, benzoxazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, or quinolinyl are optionally substituted with C(O)C₍₁₋₄₎alkyl, C(O)NH₂, C₍₁₋₄₎alkyl, CF₃, CH₂CF₃, Cl, F, —CN, OC₍₁₋₄₎alkyl, N(C₍₁₋₄₎alkyl)₂, —(CH₂)₃OCH₃, SC₍₁₋₄₎alkyl, OH, CO₂H, CO₂C₍₁₋₄₎alkyl, OCF₃, OCHF₂, SO₂CH₃, SO₂NH₂, or OCH₂OCH₃; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, and F; and wherein said triazolyl, oxazolyl, isoxazolyl, pyrrolyl, and thiazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to three additional substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₄₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SC₍₁₋₄₎alkyl, CF₃, F, Cl, and C₍₁₋₄₎alkyl; R² is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C₍₁₋₃₎alkyl-piperidinyl, thiazolyl, pyridazyl, pyrazinyl, 1-(3-methoxypropyl)-imidazolyl, or 1-C₍₁₋₂₎alkyl imidazolyl; wherein said 1-C₍₁₋₂₎alkyl imidazolyl is optionally substituted with up to two additional substituents independently selected from the group consisting of C₍₁₋₂₎alkyl, SCH₃, OC₍₁₋₂₎alkyl, CF₃, —CN, F, and Cl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to three additional substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl; and said thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OC₍₁₋₂₎alkyl, (CH₂)₍₂₋₃₎OCH₃, SCH₃, CF₃, F, Cl, and C₍₁₋₂₎alkyl; and said 1-methyl pyrazolyl is optionally substituted with up to two additional CH₃ groups; R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl, —N(CO₂C(CH₃)₃)phenyl, N(COCH₃)phenyl, —O-pyridyl, —NHpyridyl, —N(C₍₁₋₃₎alkyl)pyridyl, N(CO₂C(CH₃)₃)pyridyl, N(COCH₃)pyridyl, —O-pyrimidinyl, —NHpyrimidinyl, —N(C₍₁₋₃₎alkyl)pyrimidinyl, N(CO₂C(CH₃)₃)pyrimidinyl, N(COCH₃)pyrimidinyl, —O-pyridazyl, —NHpyridazyl, —N(C₍₁₋₃₎alkyl)pyridazyl, N(CO₂C(CH₃)₃)pyridazyl, N(COCH₃)pyridazyl, —O-pyrazinyl, —NHpyrazinyl, —N(C₍₁₋₃₎alkyl)pyrazinyl, N(CO₂C(CH₃)₃)pyrazinyl, or N(COCH₃)pyrazinyl; wherein said phenyl or said pyridyl is optionally substituted with OCF₃, SO₂C₍₁₋₄₎alkyl, CF₃, CHF₂, pyrazolyl, triazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, C₍₁₋₄₎alkyl, C₍₃₋₄₎cycloalkyl, OC₍₁₋₄₎alkyl, N(CH₃)₂, SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂, CONH₂, CONHCH₃, CON(CH₃)₂, Cl, F, —CN, CO₂H, OH, CH₂OH, NHCOC₍₁₋₂₎alkyl, COC₍₁₋₂₎alkyl, or SCH₃; R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₄₎alkylCF₃, OCH₂CH₂OC₍₁₋₄₎alkyl, CF₃, SCH₃, CH₂NA¹A², CH₂OC₍₂₋₃₎alkylNA¹A², NA¹A², C(O)NA¹A², N(CH₃)C₍₂₋₄₎alkylNA¹A², OC₍₂₋₄₎alkylNA¹A², OC₍₁₋₄₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, or pyrimidinyl; wherein said imidazolyl or pyrazolyl is optionally substituted with one CH₃ group; A¹ is H, or C₍₁₋₄₎alkyl; A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₄₎alkyl, or OC₍₁₋₄₎alkyl; or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

R_(a) is H, OC₍₁₋₄₎alkyl, CH₂OH, NH(CH₃), N(CH₃)₂, NH₂, CH₃, F, or OH; R_(b) is H, CO₂C(CH₃)₃, C₍₁₋₄₎alkyl, C(O)C₍₁₋₄₎alkyl, SO₂C₍₁₋₄₎alkyl, CH₂CH₂CF₃, CH₂CF₃, CH₂-cyclopropyl, phenyl, CH₂-phenyl, or C₍₃₋₆₎cycloalkyl; R⁸ is H, CH₃, OCH₃, or F; and pharmaceutically acceptable salts thereof.
 3. A compound of claim 2 wherein: R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolyl, and pyrazolyl are optionally substituted with C(O)C₍₁₋₄₎alkyl, C(O)NH₂, C₍₁₋₄₎alkyl, CF₃, CH₂CF₃, Cl, F, —CN, OC₍₁₋₄₎alkyl, N(C₍₁₋₄₎alkyl)₂,-(CH₂)₃OCH₃, SC₍₁₋₄₎alkyl, OH, CO₂H, CO₂C₍₁₋₄₎alkyl, OCF₃, OCHF₂, SO₂CH₃, SO₂NH₂, or OCH₂OCH₃; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH₃ groups; R² is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazolyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C₍₁₋₂₎alkyl-piperidinyl, thiazolyl, pyridazyl, 1-(3-methoxypropyl)-imidazolyl, or 1-C₍₁₋₂₎alkyl imidazolyl; wherein said 1-C₍₁₋₂₎alkyl imidazolyl is optionally substituted with up to two additional CH₃ groups, or one substituent selected from the group consisting of SCH₃, and Cl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two subsitutents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —CN, OCH₃, CF₃, Cl, and CH₃; and said thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two CH₃ groups; and said 1-methyl pyrazolyl is optionally substituted with up to two additional CH₃ groups; R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl, —N(CO₂C(CH₃)₃)phenyl, N(COCH₃)phenyl, —O-pyridyl, —NHpyridyl, —N(C₍₁₋₃₎alkyl)pyridyl, N(CO₂C(CH₃)₃)pyridyl, N(COCH₃)pyridyl, —O-pyrimidinyl, —NHpyrimidinyl, —N(C₍₁₋₃₎alkyl)pyrimidinyl, N(CO₂C(CH₃)₃)pyrimidinyl, N(COCH₃)pyrimidinyl, —O-pyridazyl, —NHpyridazyl, —N(C₍₁₋₃₎alkyl)pyridazyl, N(CO₂C(CH₃)₃)pyridazyl, N(COCH₃)pyridazyl, —O-pyrazinyl, —NHpyrazinyl, —N(C₍₁₋₃₎alkyl)pyrazinyl, N(CO₂C(CH₃)₃)pyrazinyl, or N(COCH₃)pyrazinyl wherein said phenyl or said pyridyl is optionally substituted with OCF₃, SO₂CH₃, CF₃, CHF₂, pyrazolyl, triazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, CH₃, OCH₃, N(CH₃)₂, SO₂NH₂, CONH₂, Cl, F,—CN, CO₂H, OH, CH₂OH, NHCOCH₃, or COCH₃; R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₄₎alkylCF₃, OCH₂CH₂OC₍₁₋₄₎alkyl, CF₃, SCH₃, NA¹A², C(O)NA¹A², N(CH₃)C₍₂₋₄₎alkylNA¹A², OC₍₂₋₄₎alkylNA¹A², OC₍₁₋₄₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl, imidazolyl, furyl, pyrazolyl, pyridyl, or pyrimidinyl; wherein said imidazolyl or pyrazolyl is optionally substituted with one CH₃ group; A¹ is H, or C₍₁₋₄₎alkyl; A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₄₎alkyl, or OC₍₁₋₄₎alkyl; or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

R_(a). is H, F, OC₍₁₋₄₎alkyl, or OH; R_(b) is C₍₁₋₄₎alkyl, C(O)CH₃, or phenyl; and pharmaceutically acceptable salts thereof.
 4. A compound of claim 3 wherein: R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolyl, and pyrazolyl are optionally substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl, F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃, or OCH₂OCH₃; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH₃ groups; R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C₍₁₋₂₎alkyl-piperidinyl, thiazol-5-yl, 1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl imidazol-5-yl; wherein said 1-C₍₁₋₂₎alkyl imidazol-5-yl is optionally substituted with up to two additional CH₃ groups, or one substituent selected from the group consisting of SCH₃, and Cl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two substituents independently selected from the group consisting of C(O)NH₂, —CN, OCH₃, CF₃, Cl, and CH₃; and said thiazol-5-yl, and said isoxazolyl are optionally substituted with up to two CH₃ groups; and said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH₃ groups; R⁵ is H, Cl, —CN, CF₃, SCH₃, OC₍₁₋₃₎alkyl, OH, C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl), N(C₍₁₋₂₎alkyl)₂, or 4-hydroxy-piperidinyl; R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl, —N(CO₂C(CH₃)₃)phenyl, —O-pyridyl, —NHpyridyl, —N(C₍₁₋₃₎alkyl)pyridyl, or —N(CO₂C(CH₃)₃)pyridyl wherein said phenyl or said pyridyl is optionally substituted with OCF₃, SO₂CH₃, CF₃, CHF₂, imidazol-l-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, CH₃, OCH₃, Cl, F, or —CN; R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃, NA¹A², C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A², OCH₂CH₂NA¹A², OC₍₁₋₃₎alkyl, OCH₂-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl; wherein said imidazolyl or pyrazolyl is optionally substituted with one CH₃ group; A¹ is H, or C₍₁₋₄₎alkyl; A² is H, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₂₎alkyl, or OCH₃; or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

R_(a) is H, F, OCH₃, or OH; R_(b) is CH₃, or phenyl; and pharmaceutically acceptable salts thereof.
 5. A compound of claim 4 wherein: R¹ is thiazolyl, pyridyl, or phenyl; wherein said pyridyl, and said phenyl, are optionally substituted with CF₃, Cl, or OCH₃; R² is pyrid-3-yl, or 1-methyl imidazol-5-yl; R³ is OH; R⁴ is H; R⁵ is Cl, —CN, CF₃, or OC₍₁₋₂₎alkyl; R⁶ is —O-phenyl, —NHphenyl, —N(C₍₁₋₃₎alkyl)phenyl, or —N(CO₂C(CH₃)₃)phenyl; wherein said —O-phenyl is optionally substituted with Cl, F, or —CN; R⁷ is Cl, —CN, NA¹A², or OC₍₁₋₂₎alkyl; A¹ is C₍₁₋₂₎alkyl; A² is C₍₁₋₂₎alkyl, or CH₂CH₂OCH₃; or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

R⁸ is H; R⁹ is H; and pharmaceutically acceptable salts thereof.
 6. A compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 7. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 8. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
 9. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
 10. A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1, wherein the disease is selected from the group consisting of: rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis.
 11. The method of claim 10, wherein the disease is psoriasis.
 12. The method of claim 10, wherein the disease is rheumatoid arthritis.
 13. The method of claim 10, wherein the disease is ulcerative colitis.
 14. The method of claim 10, wherein the disease is Crohn's disease.
 15. The method of claim 10, wherein the disease is multiple sclerosis.
 16. The method of claim 10, wherein the disease is neutrophilic asthma.
 17. The method of claim 10, wherein the disease is steroid resistant asthma.
 18. The method of claim 10, wherein the disease is psoriatic arthritis.
 19. The method of claim 10, wherein the disease is ankylosing spondylitis.
 20. The method of claim 10, wherein the disease is systemic lupus erythematosus.
 21. The method of claim 10, wherein the disease is chronic obstructive pulmonary disorder.
 22. A method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 1 or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis.
 23. A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 6, wherein the disease is selected from the group consisting of: rheumatoid arthritis and psoriasis.
 24. A method of inhibiting production of interleukin-17, comprising administering to a subject in need thereof an effective amount of a compound of claim
 1. 